WO2013005755A1 - Methylpiperidine derivative - Google Patents
Methylpiperidine derivative Download PDFInfo
- Publication number
- WO2013005755A1 WO2013005755A1 PCT/JP2012/067038 JP2012067038W WO2013005755A1 WO 2013005755 A1 WO2013005755 A1 WO 2013005755A1 JP 2012067038 W JP2012067038 W JP 2012067038W WO 2013005755 A1 WO2013005755 A1 WO 2013005755A1
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- WO
- WIPO (PCT)
- Prior art keywords
- group
- mmol
- pharmaceutically acceptable
- acceptable salt
- compound
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- PAMIQIKDUOTOBW-UHFFFAOYSA-N 1-methylpiperidine Chemical class CN1CCCCC1 PAMIQIKDUOTOBW-UHFFFAOYSA-N 0.000 title claims description 24
- 150000003839 salts Chemical class 0.000 claims abstract description 34
- 208000037265 diseases, disorders, signs and symptoms Diseases 0.000 claims abstract description 19
- 201000010099 disease Diseases 0.000 claims abstract description 14
- 208000019116 sleep disease Diseases 0.000 claims abstract description 7
- 208000020685 sleep-wake disease Diseases 0.000 claims abstract description 6
- 208000024827 Alzheimer disease Diseases 0.000 claims abstract description 5
- 208000019901 Anxiety disease Diseases 0.000 claims abstract description 5
- 208000030814 Eating disease Diseases 0.000 claims abstract description 5
- 208000019454 Feeding and Eating disease Diseases 0.000 claims abstract description 5
- 206010019233 Headaches Diseases 0.000 claims abstract description 5
- 208000023105 Huntington disease Diseases 0.000 claims abstract description 5
- 206010020772 Hypertension Diseases 0.000 claims abstract description 5
- 206010061218 Inflammation Diseases 0.000 claims abstract description 5
- 208000019695 Migraine disease Diseases 0.000 claims abstract description 5
- 208000002193 Pain Diseases 0.000 claims abstract description 5
- 208000018737 Parkinson disease Diseases 0.000 claims abstract description 5
- 235000014632 disordered eating Nutrition 0.000 claims abstract description 5
- 206010013663 drug dependence Diseases 0.000 claims abstract description 5
- 230000002124 endocrine Effects 0.000 claims abstract description 5
- 206010015037 epilepsy Diseases 0.000 claims abstract description 5
- 231100000869 headache Toxicity 0.000 claims abstract description 5
- 230000004054 inflammatory process Effects 0.000 claims abstract description 5
- 206010027599 migraine Diseases 0.000 claims abstract description 5
- 208000019906 panic disease Diseases 0.000 claims abstract description 5
- 201000000980 schizophrenia Diseases 0.000 claims abstract description 5
- 208000011117 substance-related disease Diseases 0.000 claims abstract description 5
- 125000005843 halogen group Chemical group 0.000 claims description 37
- 125000004169 (C1-C6) alkyl group Chemical group 0.000 claims description 29
- 125000004435 hydrogen atom Chemical group [H]* 0.000 claims description 20
- 125000004191 (C1-C6) alkoxy group Chemical group 0.000 claims description 19
- 125000004433 nitrogen atom Chemical group N* 0.000 claims description 13
- 229910052757 nitrogen Inorganic materials 0.000 claims description 12
- 125000000714 pyrimidinyl group Chemical group 0.000 claims description 10
- 125000001072 heteroaryl group Chemical group 0.000 claims description 9
- 125000001425 triazolyl group Chemical group 0.000 claims description 8
- 125000004093 cyano group Chemical group *C#N 0.000 claims description 7
- 239000004480 active ingredient Substances 0.000 claims description 5
- 239000003795 chemical substances by application Substances 0.000 claims description 5
- 208000035475 disorder Diseases 0.000 claims description 5
- 125000001424 substituent group Chemical group 0.000 claims description 4
- 125000003545 alkoxy group Chemical group 0.000 claims description 3
- 230000001079 digestive effect Effects 0.000 claims description 3
- 239000003814 drug Substances 0.000 claims description 3
- 230000000069 prophylactic effect Effects 0.000 claims description 2
- 230000001225 therapeutic effect Effects 0.000 claims description 2
- 150000001875 compounds Chemical class 0.000 abstract description 153
- 102000002512 Orexin Human genes 0.000 abstract description 17
- 108060005714 orexin Proteins 0.000 abstract description 17
- 230000003042 antagnostic effect Effects 0.000 abstract description 9
- 208000018522 Gastrointestinal disease Diseases 0.000 abstract 1
- 230000006806 disease prevention Effects 0.000 abstract 1
- XEKOWRVHYACXOJ-UHFFFAOYSA-N Ethyl acetate Chemical compound CCOC(C)=O XEKOWRVHYACXOJ-UHFFFAOYSA-N 0.000 description 86
- 239000000243 solution Substances 0.000 description 65
- VLKZOEOYAKHREP-UHFFFAOYSA-N n-Hexane Chemical compound CCCCCC VLKZOEOYAKHREP-UHFFFAOYSA-N 0.000 description 63
- 239000000203 mixture Substances 0.000 description 60
- -1 for example Chemical class 0.000 description 56
- 238000001819 mass spectrum Methods 0.000 description 48
- 235000019439 ethyl acetate Nutrition 0.000 description 42
- 239000007787 solid Substances 0.000 description 34
- 230000014759 maintenance of location Effects 0.000 description 33
- 238000006243 chemical reaction Methods 0.000 description 32
- 230000002829 reductive effect Effects 0.000 description 28
- VEXZGXHMUGYJMC-UHFFFAOYSA-N Hydrochloric acid Chemical compound Cl VEXZGXHMUGYJMC-UHFFFAOYSA-N 0.000 description 26
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 description 25
- 239000002904 solvent Substances 0.000 description 24
- 239000007788 liquid Substances 0.000 description 23
- WEVYAHXRMPXWCK-UHFFFAOYSA-N Acetonitrile Chemical compound CC#N WEVYAHXRMPXWCK-UHFFFAOYSA-N 0.000 description 22
- WYURNTSHIVDZCO-UHFFFAOYSA-N Tetrahydrofuran Chemical compound C1CCOC1 WYURNTSHIVDZCO-UHFFFAOYSA-N 0.000 description 21
- ZMANZCXQSJIPKH-UHFFFAOYSA-N Triethylamine Chemical compound CCN(CC)CC ZMANZCXQSJIPKH-UHFFFAOYSA-N 0.000 description 21
- ZMXDDKWLCZADIW-UHFFFAOYSA-N N,N-Dimethylformamide Chemical compound CN(C)C=O ZMXDDKWLCZADIW-UHFFFAOYSA-N 0.000 description 20
- OKKJLVBELUTLKV-UHFFFAOYSA-N Methanol Chemical compound OC OKKJLVBELUTLKV-UHFFFAOYSA-N 0.000 description 18
- HEMHJVSKTPXQMS-UHFFFAOYSA-M Sodium hydroxide Chemical compound [OH-].[Na+] HEMHJVSKTPXQMS-UHFFFAOYSA-M 0.000 description 18
- 238000002514 liquid chromatography mass spectrum Methods 0.000 description 18
- WSFSSNUMVMOOMR-BJUDXGSMSA-N methanone Chemical compound O=[11CH2] WSFSSNUMVMOOMR-BJUDXGSMSA-N 0.000 description 18
- 238000004440 column chromatography Methods 0.000 description 17
- JGFZNNIVVJXRND-UHFFFAOYSA-N N,N-Diisopropylethylamine (DIPEA) Chemical compound CCN(C(C)C)C(C)C JGFZNNIVVJXRND-UHFFFAOYSA-N 0.000 description 16
- 239000012044 organic layer Substances 0.000 description 16
- 125000001997 phenyl group Chemical group [H]C1=C([H])C([H])=C(*)C([H])=C1[H] 0.000 description 16
- 239000002274 desiccant Substances 0.000 description 15
- 108050000742 Orexin Receptor Proteins 0.000 description 13
- 102000008834 Orexin receptor Human genes 0.000 description 13
- 102000005962 receptors Human genes 0.000 description 13
- 108020003175 receptors Proteins 0.000 description 13
- DTQVDTLACAAQTR-UHFFFAOYSA-N Trifluoroacetic acid Chemical compound OC(=O)C(F)(F)F DTQVDTLACAAQTR-UHFFFAOYSA-N 0.000 description 12
- BDAGIHXWWSANSR-UHFFFAOYSA-N methanoic acid Natural products OC=O BDAGIHXWWSANSR-UHFFFAOYSA-N 0.000 description 12
- LMDZBCPBFSXMTL-UHFFFAOYSA-N 1-ethyl-3-(3-dimethylaminopropyl)carbodiimide Chemical compound CCN=C=NCCCN(C)C LMDZBCPBFSXMTL-UHFFFAOYSA-N 0.000 description 11
- 239000011541 reaction mixture Substances 0.000 description 11
- 238000006482 condensation reaction Methods 0.000 description 10
- YLQBMQCUIZJEEH-UHFFFAOYSA-N tetrahydrofuran Natural products C=1C=COC=1 YLQBMQCUIZJEEH-UHFFFAOYSA-N 0.000 description 10
- WMFOQBRAJBCJND-UHFFFAOYSA-M Lithium hydroxide Chemical compound [Li+].[OH-] WMFOQBRAJBCJND-UHFFFAOYSA-M 0.000 description 9
- WPYMKLBDIGXBTP-UHFFFAOYSA-N benzoic acid Chemical compound OC(=O)C1=CC=CC=C1 WPYMKLBDIGXBTP-UHFFFAOYSA-N 0.000 description 9
- 238000012360 testing method Methods 0.000 description 9
- NPJRNIZGSITPRO-UHFFFAOYSA-N 5-chloro-2-(6-methylpiperidin-3-yl)-1,3-benzoxazole Chemical compound C1NC(C)CCC1C1=NC2=CC(Cl)=CC=C2O1 NPJRNIZGSITPRO-UHFFFAOYSA-N 0.000 description 8
- JUJWROOIHBZHMG-UHFFFAOYSA-N Pyridine Chemical compound C1=CC=NC=C1 JUJWROOIHBZHMG-UHFFFAOYSA-N 0.000 description 8
- 125000000246 pyrimidin-2-yl group Chemical group [H]C1=NC(*)=NC([H])=C1[H] 0.000 description 8
- 239000007858 starting material Substances 0.000 description 8
- FYSNRJHAOHDILO-UHFFFAOYSA-N thionyl chloride Chemical compound ClS(Cl)=O FYSNRJHAOHDILO-UHFFFAOYSA-N 0.000 description 8
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Substances O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 8
- 125000001153 fluoro group Chemical group F* 0.000 description 7
- 238000000034 method Methods 0.000 description 7
- 210000005036 nerve Anatomy 0.000 description 7
- 239000002994 raw material Substances 0.000 description 7
- TZCMQIKRCZLVQN-RKDXNWHRSA-N (3r,6r)-6-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound C[C@@H]1CC[C@@H](C(O)=O)CN1C(=O)OC(C)(C)C TZCMQIKRCZLVQN-RKDXNWHRSA-N 0.000 description 6
- PAQZWJGSJMLPMG-UHFFFAOYSA-N 2,4,6-tripropyl-1,3,5,2$l^{5},4$l^{5},6$l^{5}-trioxatriphosphinane 2,4,6-trioxide Chemical compound CCCP1(=O)OP(=O)(CCC)OP(=O)(CCC)O1 PAQZWJGSJMLPMG-UHFFFAOYSA-N 0.000 description 6
- OSWFIVFLDKOXQC-UHFFFAOYSA-N 4-(3-methoxyphenyl)aniline Chemical compound COC1=CC=CC(C=2C=CC(N)=CC=2)=C1 OSWFIVFLDKOXQC-UHFFFAOYSA-N 0.000 description 6
- TZCMQIKRCZLVQN-UHFFFAOYSA-N 6-methyl-1-[(2-methylpropan-2-yl)oxycarbonyl]piperidine-3-carboxylic acid Chemical compound CC1CCC(C(O)=O)CN1C(=O)OC(C)(C)C TZCMQIKRCZLVQN-UHFFFAOYSA-N 0.000 description 6
- QTBSBXVTEAMEQO-UHFFFAOYSA-N Acetic acid Chemical compound CC(O)=O QTBSBXVTEAMEQO-UHFFFAOYSA-N 0.000 description 6
- HEDRZPFGACZZDS-UHFFFAOYSA-N Chloroform Chemical compound ClC(Cl)Cl HEDRZPFGACZZDS-UHFFFAOYSA-N 0.000 description 6
- QAOWNCQODCNURD-UHFFFAOYSA-N Sulfuric acid Chemical compound OS(O)(=O)=O QAOWNCQODCNURD-UHFFFAOYSA-N 0.000 description 6
- YXFVVABEGXRONW-UHFFFAOYSA-N Toluene Chemical compound CC1=CC=CC=C1 YXFVVABEGXRONW-UHFFFAOYSA-N 0.000 description 6
- 238000001035 drying Methods 0.000 description 6
- 235000019253 formic acid Nutrition 0.000 description 6
- IXCSERBJSXMMFS-UHFFFAOYSA-N hydrogen chloride Substances Cl.Cl IXCSERBJSXMMFS-UHFFFAOYSA-N 0.000 description 6
- 229910000041 hydrogen chloride Inorganic materials 0.000 description 6
- 239000003446 ligand Substances 0.000 description 6
- 239000005711 Benzoic acid Substances 0.000 description 5
- IAZDPXIOMUYVGZ-UHFFFAOYSA-N Dimethylsulphoxide Chemical compound CS(C)=O IAZDPXIOMUYVGZ-UHFFFAOYSA-N 0.000 description 5
- VYPSYNLAJGMNEJ-UHFFFAOYSA-N Silicium dioxide Chemical compound O=[Si]=O VYPSYNLAJGMNEJ-UHFFFAOYSA-N 0.000 description 5
- 239000002253 acid Substances 0.000 description 5
- 238000004458 analytical method Methods 0.000 description 5
- 235000010233 benzoic acid Nutrition 0.000 description 5
- 125000003236 benzoyl group Chemical group [H]C1=C([H])C([H])=C(C([H])=C1[H])C(*)=O 0.000 description 5
- 238000001514 detection method Methods 0.000 description 5
- FAMRKDQNMBBFBR-BQYQJAHWSA-N diethyl azodicarboxylate Substances CCOC(=O)\N=N\C(=O)OCC FAMRKDQNMBBFBR-BQYQJAHWSA-N 0.000 description 5
- MVEAAGBEUOMFRX-UHFFFAOYSA-N ethyl acetate;hydrochloride Chemical compound Cl.CCOC(C)=O MVEAAGBEUOMFRX-UHFFFAOYSA-N 0.000 description 5
- 229910052731 fluorine Inorganic materials 0.000 description 5
- 238000004128 high performance liquid chromatography Methods 0.000 description 5
- 239000003921 oil Substances 0.000 description 5
- 229920000137 polyphosphoric acid Polymers 0.000 description 5
- 125000006239 protecting group Chemical group 0.000 description 5
- 230000007958 sleep Effects 0.000 description 5
- ULDFRPKVIZMKJG-UHFFFAOYSA-N 2-amino-4-fluorophenol Chemical compound NC1=CC(F)=CC=C1O ULDFRPKVIZMKJG-UHFFFAOYSA-N 0.000 description 4
- BMTZEAOGFDXDAD-UHFFFAOYSA-M 4-(4,6-dimethoxy-1,3,5-triazin-2-yl)-4-methylmorpholin-4-ium;chloride Chemical compound [Cl-].COC1=NC(OC)=NC([N+]2(C)CCOCC2)=N1 BMTZEAOGFDXDAD-UHFFFAOYSA-M 0.000 description 4
- LXBXYUWUCKQXKE-UHFFFAOYSA-N 5-fluoro-2-(6-methylpiperidin-3-yl)-1,3-benzoxazole Chemical compound C1NC(C)CCC1C1=NC2=CC(F)=CC=C2O1 LXBXYUWUCKQXKE-UHFFFAOYSA-N 0.000 description 4
- 239000007821 HATU Substances 0.000 description 4
- AFVFQIVMOAPDHO-UHFFFAOYSA-N Methanesulfonic acid Chemical compound CS(O)(=O)=O AFVFQIVMOAPDHO-UHFFFAOYSA-N 0.000 description 4
- 239000007864 aqueous solution Substances 0.000 description 4
- 239000012131 assay buffer Substances 0.000 description 4
- 238000000065 atmospheric pressure chemical ionisation Methods 0.000 description 4
- 125000004432 carbon atom Chemical group C* 0.000 description 4
- 238000000605 extraction Methods 0.000 description 4
- NPZTUJOABDZTLV-UHFFFAOYSA-N hydroxybenzotriazole Substances O=C1C=CC=C2NNN=C12 NPZTUJOABDZTLV-UHFFFAOYSA-N 0.000 description 4
- 238000000752 ionisation method Methods 0.000 description 4
- 239000012046 mixed solvent Substances 0.000 description 4
- BVOCPVIXARZNQN-UHFFFAOYSA-N nipecotamide Chemical compound NC(=O)C1CCCNC1 BVOCPVIXARZNQN-UHFFFAOYSA-N 0.000 description 4
- SIOXPEMLGUPBBT-UHFFFAOYSA-N picolinic acid Chemical compound OC(=O)C1=CC=CC=N1 SIOXPEMLGUPBBT-UHFFFAOYSA-N 0.000 description 4
- UMJSCPRVCHMLSP-UHFFFAOYSA-N pyridine Natural products COC1=CC=CN=C1 UMJSCPRVCHMLSP-UHFFFAOYSA-N 0.000 description 4
- 238000010992 reflux Methods 0.000 description 4
- 239000011734 sodium Substances 0.000 description 4
- 239000000126 substance Substances 0.000 description 4
- 125000005931 tert-butyloxycarbonyl group Chemical group [H]C([H])([H])C(OC(*)=O)(C([H])([H])[H])C([H])([H])[H] 0.000 description 4
- FPGGTKZVZWFYPV-UHFFFAOYSA-M tetrabutylammonium fluoride Chemical compound [F-].CCCC[N+](CCCC)(CCCC)CCCC FPGGTKZVZWFYPV-UHFFFAOYSA-M 0.000 description 4
- JOXIMZWYDAKGHI-UHFFFAOYSA-N toluene-4-sulfonic acid Chemical compound CC1=CC=C(S(O)(=O)=O)C=C1 JOXIMZWYDAKGHI-UHFFFAOYSA-N 0.000 description 4
- RIOQSEWOXXDEQQ-UHFFFAOYSA-N triphenylphosphine Chemical compound C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 RIOQSEWOXXDEQQ-UHFFFAOYSA-N 0.000 description 4
- RYHBNJHYFVUHQT-UHFFFAOYSA-N 1,4-Dioxane Chemical compound C1COCCO1 RYHBNJHYFVUHQT-UHFFFAOYSA-N 0.000 description 3
- QWENRTYMTSOGBR-UHFFFAOYSA-N 1H-1,2,3-Triazole Chemical compound C=1C=NNN=1 QWENRTYMTSOGBR-UHFFFAOYSA-N 0.000 description 3
- ACWUXIWHMGKPIR-UHFFFAOYSA-N 5-methyl-2-pyrimidin-2-ylbenzaldehyde Chemical compound O=CC1=CC(C)=CC=C1C1=NC=CC=N1 ACWUXIWHMGKPIR-UHFFFAOYSA-N 0.000 description 3
- USLXSKZTJPBDAD-UHFFFAOYSA-N 6-methyl-1-[5-methyl-2-(triazol-2-yl)benzoyl]piperidine-3-carboxylic acid Chemical compound CC1CCC(C(O)=O)CN1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 USLXSKZTJPBDAD-UHFFFAOYSA-N 0.000 description 3
- VZIMHMHXWWFNHP-UHFFFAOYSA-N CC1=CC=C(C(=N1)C=O)N1N=CC=N1 Chemical compound CC1=CC=C(C(=N1)C=O)N1N=CC=N1 VZIMHMHXWWFNHP-UHFFFAOYSA-N 0.000 description 3
- YMWUJEATGCHHMB-UHFFFAOYSA-N Dichloromethane Chemical compound ClCCl YMWUJEATGCHHMB-UHFFFAOYSA-N 0.000 description 3
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- LTGVIMBNYBDWGE-HUUCEWRRSA-N [(2r,5r)-5-(5-chloro-1,3-benzoxazol-2-yl)-2-methylpiperidin-1-yl]-[6-methyl-3-(triazol-2-yl)pyridin-2-yl]methanone Chemical compound C([C@@H](CC[C@H]1C)C=2OC3=CC=C(Cl)C=C3N=2)N1C(=O)C1=NC(C)=CC=C1N1N=CC=N1 LTGVIMBNYBDWGE-HUUCEWRRSA-N 0.000 description 3
- 210000004027 cell Anatomy 0.000 description 3
- 229910052801 chlorine Inorganic materials 0.000 description 3
- 125000001309 chloro group Chemical group Cl* 0.000 description 3
- KRKNYBCHXYNGOX-UHFFFAOYSA-N citric acid Chemical compound OC(=O)CC(O)(C(O)=O)CC(O)=O KRKNYBCHXYNGOX-UHFFFAOYSA-N 0.000 description 3
- 238000004519 manufacturing process Methods 0.000 description 3
- 238000012746 preparative thin layer chromatography Methods 0.000 description 3
- 230000036385 rapid eye movement (rem) sleep Effects 0.000 description 3
- 238000007363 ring formation reaction Methods 0.000 description 3
- MEKOFIRRDATTAG-UHFFFAOYSA-N 2,2,5,8-tetramethyl-3,4-dihydrochromen-6-ol Chemical compound C1CC(C)(C)OC2=C1C(C)=C(O)C=C2C MEKOFIRRDATTAG-UHFFFAOYSA-N 0.000 description 2
- GXCBYDCDBQWJFX-UHFFFAOYSA-N 2-(triazol-2-yl)benzaldehyde Chemical compound O=CC1=CC=CC=C1N1N=CC=N1 GXCBYDCDBQWJFX-UHFFFAOYSA-N 0.000 description 2
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- 125000004105 2-pyridyl group Chemical group N1=C([*])C([H])=C([H])C([H])=C1[H] 0.000 description 2
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- UIJBMVGLKKCQFX-UHFFFAOYSA-N 3-amino-5-chloro-1h-pyridin-2-one;hydrochloride Chemical compound Cl.NC1=CC(Cl)=CN=C1O UIJBMVGLKKCQFX-UHFFFAOYSA-N 0.000 description 2
- NPJRNIZGSITPRO-RKDXNWHRSA-N 5-chloro-2-[(3r,6r)-6-methylpiperidin-3-yl]-1,3-benzoxazole Chemical compound C1N[C@H](C)CC[C@H]1C1=NC2=CC(Cl)=CC=C2O1 NPJRNIZGSITPRO-RKDXNWHRSA-N 0.000 description 2
- WKDHORIIWZFUCN-UHFFFAOYSA-N 5-fluoro-2-pyrimidin-2-ylbenzaldehyde Chemical compound O=CC1=CC(F)=CC=C1C1=NC=CC=N1 WKDHORIIWZFUCN-UHFFFAOYSA-N 0.000 description 2
- RDBXBVVGBXXYNE-UHFFFAOYSA-N 5-methyl-2-(triazol-2-yl)benzaldehyde Chemical compound O=CC1=CC(C)=CC=C1N1N=CC=N1 RDBXBVVGBXXYNE-UHFFFAOYSA-N 0.000 description 2
- NFAMTPGPWJKQOG-UHFFFAOYSA-N 6-fluoro-2-(6-methylpiperidin-3-yl)-1,3-benzoxazole;hydrochloride Chemical compound Cl.C1NC(C)CCC1C1=NC2=CC=C(F)C=C2O1 NFAMTPGPWJKQOG-UHFFFAOYSA-N 0.000 description 2
- HYMIXLCBOZRYAV-UHFFFAOYSA-N 6-methyl-3-(triazol-2-yl)pyridine-2-carboxylic acid Chemical compound OC(=O)C1=NC(C)=CC=C1N1N=CC=N1 HYMIXLCBOZRYAV-UHFFFAOYSA-N 0.000 description 2
- BYWWIDLMCZNAIS-UHFFFAOYSA-N 6-methyl-3-pyrimidin-2-ylpyridine-2-carbaldehyde Chemical compound O=CC1=NC(C)=CC=C1C1=NC=CC=N1 BYWWIDLMCZNAIS-UHFFFAOYSA-N 0.000 description 2
- ZCYVEMRRCGMTRW-UHFFFAOYSA-N 7553-56-2 Chemical group [I] ZCYVEMRRCGMTRW-UHFFFAOYSA-N 0.000 description 2
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- NTYJJOPFIAHURM-UHFFFAOYSA-N Histamine Chemical compound NCCC1=CN=CN1 NTYJJOPFIAHURM-UHFFFAOYSA-N 0.000 description 2
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- TWRXJAOTZQYOKJ-UHFFFAOYSA-L Magnesium chloride Chemical compound [Mg+2].[Cl-].[Cl-] TWRXJAOTZQYOKJ-UHFFFAOYSA-L 0.000 description 2
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- CDBYLPFSWZWCQE-UHFFFAOYSA-L Sodium Carbonate Chemical compound [Na+].[Na+].[O-]C([O-])=O CDBYLPFSWZWCQE-UHFFFAOYSA-L 0.000 description 2
- UIIMBOGNXHQVGW-UHFFFAOYSA-M Sodium bicarbonate Chemical compound [Na+].OC([O-])=O UIIMBOGNXHQVGW-UHFFFAOYSA-M 0.000 description 2
- 239000012317 TBTU Substances 0.000 description 2
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- 210000004185 liver Anatomy 0.000 description 1
- 210000000627 locus coeruleus Anatomy 0.000 description 1
- 231100000053 low toxicity Toxicity 0.000 description 1
- 239000000314 lubricant Substances 0.000 description 1
- 229910001629 magnesium chloride Inorganic materials 0.000 description 1
- 235000019359 magnesium stearate Nutrition 0.000 description 1
- VZCYOOQTPOCHFL-UPHRSURJSA-N maleic acid Chemical compound OC(=O)\C=C/C(O)=O VZCYOOQTPOCHFL-UPHRSURJSA-N 0.000 description 1
- 239000011976 maleic acid Substances 0.000 description 1
- 239000001630 malic acid Substances 0.000 description 1
- 235000011090 malic acid Nutrition 0.000 description 1
- 229960002510 mandelic acid Drugs 0.000 description 1
- 239000000594 mannitol Substances 0.000 description 1
- 235000010355 mannitol Nutrition 0.000 description 1
- 238000005259 measurement Methods 0.000 description 1
- 230000037323 metabolic rate Effects 0.000 description 1
- VAUIDGILAZCFMS-UHFFFAOYSA-N methyl 6-methyl-1-[5-methyl-2-(triazol-2-yl)benzoyl]piperidine-3-carboxylate Chemical compound C1C(C(=O)OC)CCC(C)N1C(=O)C1=CC(C)=CC=C1N1N=CC=N1 VAUIDGILAZCFMS-UHFFFAOYSA-N 0.000 description 1
- 235000010755 mineral Nutrition 0.000 description 1
- 239000011707 mineral Substances 0.000 description 1
- 150000007522 mineralic acids Chemical class 0.000 description 1
- 125000004108 n-butyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001280 n-hexyl group Chemical group C(CCCCC)* 0.000 description 1
- 125000000740 n-pentyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000004123 n-propyl group Chemical group [H]C([H])([H])C([H])([H])C([H])([H])* 0.000 description 1
- KVBGVZZKJNLNJU-UHFFFAOYSA-N naphthalene-2-sulfonic acid Chemical compound C1=CC=CC2=CC(S(=O)(=O)O)=CC=C21 KVBGVZZKJNLNJU-UHFFFAOYSA-N 0.000 description 1
- 125000005244 neohexyl group Chemical group [H]C([H])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])C([H])([H])* 0.000 description 1
- 125000001971 neopentyl group Chemical group [H]C([*])([H])C(C([H])([H])[H])(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 210000000653 nervous system Anatomy 0.000 description 1
- 210000002569 neuron Anatomy 0.000 description 1
- 238000006386 neutralization reaction Methods 0.000 description 1
- 229930027945 nicotinamide-adenine dinucleotide Natural products 0.000 description 1
- 229910017604 nitric acid Inorganic materials 0.000 description 1
- 230000008452 non REM sleep Effects 0.000 description 1
- 230000002474 noradrenergic effect Effects 0.000 description 1
- 239000002674 ointment Substances 0.000 description 1
- 150000007524 organic acids Chemical class 0.000 description 1
- 235000005985 organic acids Nutrition 0.000 description 1
- 210000001672 ovary Anatomy 0.000 description 1
- 235000006408 oxalic acid Nutrition 0.000 description 1
- 125000002971 oxazolyl group Chemical group 0.000 description 1
- KDLHZDBZIXYQEI-UHFFFAOYSA-N palladium Substances [Pd] KDLHZDBZIXYQEI-UHFFFAOYSA-N 0.000 description 1
- NFHFRUOZVGFOOS-UHFFFAOYSA-N palladium;triphenylphosphane Chemical compound [Pd].C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1.C1=CC=CC=C1P(C=1C=CC=CC=1)C1=CC=CC=C1 NFHFRUOZVGFOOS-UHFFFAOYSA-N 0.000 description 1
- 125000003538 pentan-3-yl group Chemical group [H]C([H])([H])C([H])([H])C([H])(*)C([H])([H])C([H])([H])[H] 0.000 description 1
- 239000000546 pharmaceutical excipient Substances 0.000 description 1
- 230000000704 physical effect Effects 0.000 description 1
- 150000003053 piperidines Chemical class 0.000 description 1
- 125000003386 piperidinyl group Chemical group 0.000 description 1
- 239000001267 polyvinylpyrrolidone Substances 0.000 description 1
- 229920000036 polyvinylpyrrolidone Polymers 0.000 description 1
- 235000013855 polyvinylpyrrolidone Nutrition 0.000 description 1
- 229910000027 potassium carbonate Inorganic materials 0.000 description 1
- WSHYKIAQCMIPTB-UHFFFAOYSA-M potassium;2-oxo-3-(3-oxo-1-phenylbutyl)chromen-4-olate Chemical compound [K+].[O-]C=1C2=CC=CC=C2OC(=O)C=1C(CC(=O)C)C1=CC=CC=C1 WSHYKIAQCMIPTB-UHFFFAOYSA-M 0.000 description 1
- DBABZHXKTCFAPX-UHFFFAOYSA-N probenecid Chemical compound CCCN(CCC)S(=O)(=O)C1=CC=C(C(O)=O)C=C1 DBABZHXKTCFAPX-UHFFFAOYSA-N 0.000 description 1
- 229960003081 probenecid Drugs 0.000 description 1
- 229940043274 prophylactic drug Drugs 0.000 description 1
- 238000000746 purification Methods 0.000 description 1
- 125000003373 pyrazinyl group Chemical group 0.000 description 1
- 125000003226 pyrazolyl group Chemical group 0.000 description 1
- 125000002098 pyridazinyl group Chemical group 0.000 description 1
- 125000004076 pyridyl group Chemical group 0.000 description 1
- 238000011002 quantification Methods 0.000 description 1
- 230000002285 radioactive effect Effects 0.000 description 1
- 210000001609 raphe nuclei Anatomy 0.000 description 1
- 239000002464 receptor antagonist Substances 0.000 description 1
- 229940044551 receptor antagonist Drugs 0.000 description 1
- 230000015355 regulation of circadian sleep/wake cycle, sleep Effects 0.000 description 1
- 238000011160 research Methods 0.000 description 1
- 238000012552 review Methods 0.000 description 1
- 229920006395 saturated elastomer Polymers 0.000 description 1
- 229940076279 serotonin Drugs 0.000 description 1
- 238000004904 shortening Methods 0.000 description 1
- 239000000377 silicon dioxide Substances 0.000 description 1
- 229910000030 sodium bicarbonate Inorganic materials 0.000 description 1
- 235000017557 sodium bicarbonate Nutrition 0.000 description 1
- 229910000033 sodium borohydride Inorganic materials 0.000 description 1
- 239000012279 sodium borohydride Substances 0.000 description 1
- 229910000029 sodium carbonate Inorganic materials 0.000 description 1
- 239000012312 sodium hydride Substances 0.000 description 1
- 230000002269 spontaneous effect Effects 0.000 description 1
- 239000008107 starch Substances 0.000 description 1
- 235000019698 starch Nutrition 0.000 description 1
- 230000000638 stimulation Effects 0.000 description 1
- 238000003756 stirring Methods 0.000 description 1
- 239000000758 substrate Substances 0.000 description 1
- 229910052717 sulfur Inorganic materials 0.000 description 1
- 125000004434 sulfur atom Chemical group 0.000 description 1
- 239000006228 supernatant Substances 0.000 description 1
- 239000000829 suppository Substances 0.000 description 1
- 239000000725 suspension Substances 0.000 description 1
- 239000003826 tablet Substances 0.000 description 1
- 239000000454 talc Substances 0.000 description 1
- 229910052623 talc Inorganic materials 0.000 description 1
- 239000011975 tartaric acid Substances 0.000 description 1
- 235000002906 tartaric acid Nutrition 0.000 description 1
- ZTQGYRCSNRILFA-VXGBXAGGSA-N tert-butyl (2r,5r)-2-methyl-5-[5-(trifluoromethyl)-1,3-benzoxazol-2-yl]piperidine-1-carboxylate Chemical compound C1N(C(=O)OC(C)(C)C)[C@H](C)CC[C@H]1C1=NC2=CC(C(F)(F)F)=CC=C2O1 ZTQGYRCSNRILFA-VXGBXAGGSA-N 0.000 description 1
- 125000001973 tert-pentyl group Chemical group [H]C([H])([H])C([H])([H])C(*)(C([H])([H])[H])C([H])([H])[H] 0.000 description 1
- 125000000335 thiazolyl group Chemical group 0.000 description 1
- 125000002023 trifluoromethyl group Chemical group FC(F)(F)* 0.000 description 1
- 210000004515 ventral tegmental area Anatomy 0.000 description 1
Classifications
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D498/00—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D498/02—Heterocyclic compounds containing in the condensed system at least one hetero ring having nitrogen and oxygen atoms as the only ring hetero atoms in which the condensed system contains two hetero rings
- C07D498/04—Ortho-condensed systems
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/04—Centrally acting analgesics, e.g. opioids
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/08—Antiepileptics; Anticonvulsants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/14—Drugs for disorders of the nervous system for treating abnormal movements, e.g. chorea, dyskinesia
- A61P25/16—Anti-Parkinson drugs
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/22—Anxiolytics
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/28—Drugs for disorders of the nervous system for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A61P25/30—Drugs for disorders of the nervous system for treating abuse or dependence
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
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- A—HUMAN NECESSITIES
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- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
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- A—HUMAN NECESSITIES
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- A—HUMAN NECESSITIES
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- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/12—Antihypertensives
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
Definitions
- the present invention relates to a compound having an orexin (OX) receptor antagonistic action and a pharmaceutically acceptable salt thereof, and sleep disorders, depressions, anxiety disorders, panic disorders, schizophrenia, drug dependence containing them as active ingredients
- OX orexin
- the present invention relates to a therapeutic or prophylactic agent for diseases such as infectious diseases, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive system diseases, epilepsy, inflammation, immune related diseases, endocrine related diseases, and hypertension.
- Orexin is a neuropeptide spliced from preproorexin that is specifically expressed in the lateral hypothalamic area. So far, OX-A consisting of 33 amino acids and OX-B consisting of 28 amino acids have been identified, both of which are deeply involved in the regulation of sleep / wake patterns and the regulation of food intake. .
- OX-A and OX-B act on the OX receptor.
- the OX receptor has been previously cloned into two subtypes of OX1 and OX2 receptors, and both are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. .
- the OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
- the tissue distribution varies depending on the subtype of the OX receptor.
- the OX1 receptor is dense in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). The orexin nerve projects to the brain stem and the monoamine nervous system of the hypothalamus and exerts an excitatory effect on those nerves. Furthermore, the expression of OX2 receptor is also seen in the acetylcholine nerve of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).
- Non-Patent Document 6 When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous movement is increased (see Non-Patent Document 6 and Non-Patent Document 7), the behavior is increased (see Non-Patent Document 7), and the awakening time is extended (Non-Patent Document). 6).
- the effect of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8).
- Patent Document 9 discloses substituted piperidine derivatives, but do not disclose a compound in which a benzoxazole ring is directly bonded to the piperidine ring described in the present application.
- the object of the present invention is to find a novel compound having an OX receptor antagonistic action, sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, feeding
- the object is to provide a therapeutic or prophylactic agent for diseases such as disorders, headaches, migraines, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, and hypertension. More specifically, it is to provide a novel compound exhibiting excellent pharmacokinetics and safety as well as excellent OX receptor antagonism.
- the present inventors have found that a certain methylpiperidine derivative represented by the following formula has an excellent OX receptor antagonistic action.
- the present invention has been completed.
- the present invention will be described in detail.
- the embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
- Formula (IA) (Where X represents a nitrogen atom or the formula CH; Y represents a nitrogen atom or the formula CH; R 1 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms), or C 1-6 alkoxy Group, R 2 represents a heteroaryl group (the heteroaryl group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group); R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and C 1-6 The alkoxy group may be substituted with 1 to 3 halogen atoms).
- R 3 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be)
- R 4 is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof
- R 2 is a triazolyl group or a pyrimidinyl group (the pyrimidinyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group).
- Y is the formula CH;
- X is a nitrogen atom
- the above formula (IA) is converted to formula (IIA)
- X is a nitrogen atom
- R 1 is a hydrogen atom or a C 1-6 alkyl group
- R 2 is a triazolyl group or a pyrimidinyl group
- the above formula (I) is converted to formula (II) A methylpiperidine derivative according to any one of (8) and (9), or a pharmaceutically acceptable salt thereof, (11)
- (12) Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia containing the methylpiperidine derivative according to any one of (1) to (10) above or a pharmaceutically acceptable salt thereof as an active ingredient
- Treatment of diseases such as infectious diseases, drug addiction, Alzheimer's disease, Parkinson'
- the methylpiperidine derivative of the present invention exhibits affinity for the OX receptor and antagonism against stimulation of the receptor by a physiological ligand.
- halogen atom is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
- C 1-6 alkyl group means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples thereof include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like.
- C 1-6 alkoxy group means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec -Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, n-hexyloxy group and the like can be mentioned.
- Heteroaryl means a 5- or 6-membered heteroaryl consisting of one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and 1 to 5 carbon atoms. Examples thereof include pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl group and the like.
- insomnia disorder refers to a disorder during sleep onset, the sleep sustaining phase, or awakening, and includes, for example, insomnia.
- insomnia classification include sleep onset disorder, mid-wake awakening, early morning awakening, and deep sleep disorder.
- “pharmaceutically acceptable salt” means a pharmaceutically acceptable acid addition salt, and the acid used includes sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid, nitric acid. Salts with inorganic acids such as acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycol And salts with organic acids such as acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, camphorsulfonic acid, naphthalene-2-sulfonic acid. Conversion from the educt to the salt can be performed by conventional methods.
- Y is preferably a compound of formula CH.
- a compound in which X is a nitrogen atom is preferable.
- R 1 is preferably a hydrogen atom, a halogen atom (excluding an iodine atom), or a C 1-6 alkyl group, wherein the halogen atom is more preferably a fluorine atom, and a C 1-6 alkyl group. More preferably, the group is a methyl group.
- R 2 is preferably a compound that is a triazolyl group or a pyrimidinyl group, and more preferably a compound that is a 1,2,3-triazol-2-yl group or a pyrimidin-2-yl group.
- R 3 represents a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms).
- a compound that is a halogen atom or a C 1-6 alkyl group (the C 1-6 alkyl group is substituted with 1 to 3 fluorine atoms) is more preferable, A compound which is a fluorine atom, a chlorine atom or a trifluoromethyl group is more preferred, and a compound which is a fluorine atom or a chlorine atom is particularly preferred.
- R 4 is preferably a compound that is a hydrogen atom or a halogen atom, and more preferably a compound that is a hydrogen atom or a fluorine atom.
- preferred compounds in the compounds of the present invention include [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone, [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone, [(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl
- the compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
- the compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and fluorine atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
- the compound according to the present invention can be administered orally or parenterally.
- the dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
- These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose).
- the compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day.
- the dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
- Desirable profiles in the compounds of the present invention include excellent drug efficacy, excellent pharmacokinetics (eg, good oral absorption), excellent physical properties, low toxicity, and the like.
- Representative schemes for producing the compound (IA) of the present invention are shown in the following schemes AC.
- the following method is an illustration of the production method of the compound of the present invention, and is not limited thereto.
- the compound may form a salt that does not hinder the reaction.
- Boc represents a tert-butoxycarbonyl group
- X, Y, R 1 , R 2 and R 3 have the same meanings as described above.
- P represents a general protecting group for a hydroxy group such as J. F. W.
- the groups described in McOmie, Protective Groups in Organic Chemistry, and T. W. Greene and PGM Wuts, Protective Groups in Organic Synthesis etc. are shown, for example, a triethylsilyl group etc.
- Step A-1 Compound (2) can be obtained by hydrolysis reaction of ester of compound (1).
- the reaction in Step A-1 uses an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide or the like as a base, and uses methanol, ethanol, tetrahydrofuran or the like as a mixed solvent for increasing the solubility of the substrate or adjusting the reaction temperature. You can also This reaction can be performed under conditions of 0 ° C. to reflux temperature.
- Step A-2 The compound (4) can be obtained by a condensation reaction of the compound (2) and the compound (3). Examples of the condensation reaction in Step A-2 include a method using a dehydrating condensing agent.
- Examples of the dehydrating condensing agent include DMT-MM (4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride), 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide / hydrochloride, propanephosphonic acid anhydride, HATU [O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate TBTU (O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate), dicyclohexylcarbodiimide, diphenylphosphonyl azide, carbonyldiimidazole, etc.
- DMT-MM (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride
- Activating agents such as 1-hydroxybenzotriazole and hydroxysuccinimide are added as necessary. It is possible to have.
- the reaction solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, toluene, ethyl acetate, methanol, ethanol, water, and a mixed solvent thereof.
- the reaction can be carried out using a base.
- the base include organic amines such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. The reaction can be carried out at 0 ° C. to reflux temperature.
- Step A-3 Compound (5) can be obtained from compound (4) by a ring-closing reaction.
- the reaction in Step A-3 is carried out in the absence of a solvent, in a solvent such as acetonitrile, tetrahydrofuran, chloroform, or a mixed solvent thereof, thionyl chloride, phosphorus oxychloride, polyphosphoric acid, acetic acid, triphenylphosphine / DEAD (diethylazo Dicarboxylate), triphenylphosphine / hexachloroethane, etc. can be used and the reaction can be carried out at 0 ° C. to reflux temperature.
- a solvent such as acetonitrile, tetrahydrofuran, chloroform, or a mixed solvent thereof
- thionyl chloride phosphorus oxychloride
- polyphosphoric acid acetic acid
- triphenylphosphine / DEAD diethylazo Dicarboxy
- Step A-4 Compound (6) can be obtained by reacting compound (5) with an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.
- an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like.
- Step A-5 Compound (8) can be obtained by a condensation reaction of compound (6) and compound (7).
- the condensation reaction in step A-5 can be carried out according to the same reaction conditions as in step A-2.
- Step B-1 The compound (10) can be obtained by a condensation reaction of the compound (9) and the compound (7).
- the condensation reaction in step B-1 can be carried out according to the same reaction conditions as in step A-2.
- Step B-2: Compound (11) can be obtained by hydrolysis reaction of ester of compound (10).
- the reaction in Step B-2 can be performed according to the same reaction conditions as in Step A-1.
- it can also be obtained by acid hydrolysis using an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid.
- a mineral acid such as hydrochloric acid or sulfuric acid.
- the solvent methanol, ethanol, 1,4-dioxane and the like can be used as a mixed solvent.
- Step B-3 Compound (12) can be obtained by a condensation reaction of compound (11) and compound (3 ′). The condensation reaction in Step B-3 can be performed according to the same reaction conditions as in Step A-2.
- Step B-4 Compound (13) can be obtained by ring-closing reaction of compound (12). The reaction in Step B-4 can be performed according to the same reaction conditions as in Step A-3.
- Scheme C
- Step C-1 Compound (14) can be obtained by cyclization reaction of Compound (2) and Compound (3 ′). The reaction in Step C-1 can be performed under conditions of 80 to 120 ° C. using an Eaton reagent as an acid catalyst.
- Step C-2 The compound (15) can be obtained by a condensation reaction of the compound (14) and the compound (7). The condensation reaction in Step C-2 can be performed according to the same reaction conditions as in Step A-2.
- KP-Sil when purified using column chromatography is Biotage's SNAP Cartridge KP-Sil, “HP-Sil” is Biotage's SNAP Cartridge HP-Sil, “KP-Sil.”
- NH Biotage SNAP Cartridge KP-NH was used.
- LCMS liquid chromatography mass spectrum
- MS measuring instrument SHIMADZU LCMS-2010EV or micromass Platform LC
- compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).
- the reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc) to obtain a racemic mixture (163 mg) of the title compound (colorless solid). The obtained racemic mixture was divided under the above racemic resolution conditions (condition 2), and two peaks (retention times under the above analysis conditions: 5.67 min, 8.58 min) were resolved.
- the title compound was obtained as a compound having a long relative retention time (retention time: 8.58 min) (colorless solid).
- the obtained title compound was derived in Reference Example 14 and the absolute steric structure was determined [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidine. -1-yl] [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone and the retention times in the chiral analysis (Condition A) were the same The absolute steric structure was confirmed. LCMS retention time 3.80 min. (Condition 3) MS (ESI pos.) M / z: 437 [M + H] +
- 6-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole hydrochloride (88.0 mg, 0.33 mmol), TEA (0.05 mL, 0.36 mmol)
- DMF solution 3 mL
- 6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridine-2-carboxylic acid 73.0 mg, 0.36 mmol
- HOBt ⁇ H 2 O 74.0 mg, 0.49 mmol
- EDC.HCl 93.0 mg, 0.49 mmol
- Examples 14 to 70 were obtained in the same manner as in Example 13 below.
- the structural formulas, compound names, and LCMS data of the obtained compounds are shown in Tables 5-1 to 5-10.
- Test Example 1 Measurement of orexin antagonistic activity
- Test compounds human orexin type 1 receptor (hOX1R), orexin type 2 receptor (hO The antagonistic activity against (X2R) was performed by modifying the method described in the literature (Toshikatsu Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001).
- Chinese hamster ovary (CHO) cells in which hOX1R and hOX2R are forcibly expressed were seeded in each well of a 96-well Black clear bottom plate (Nunc) at 20,000 cells, 0.1 mM MEM non-essential amino acids, 0.
- the cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2. After removing the medium, an assay buffer containing 25 ⁇ M Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 ⁇ L of 200 ⁇ g / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2 .
- Dojin Fluo-3AM ester
- Dojin Hanks' balanced salt solution
- bovine serum albumin 2.5 mM probenecid
- 100 ⁇ L of 200 ⁇ g / ml Amaranth above Sigma-Aldrich
- test compound was dissolved in dimethyl sulfoxide to a concentration of 10 mM, diluted with assay buffer, added with 150 ⁇ L, and incubated for 30 minutes.
- Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 300 pM for hOX1R and hOX2R Each was diluted with an assay buffer so as to be 3 nM, and 50 ⁇ L of this ligand solution was added to initiate the reaction.
- the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and the antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration.
- the antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%.
- the 50% inhibitory concentration (IC 50 value) was determined from the fluorescence value upon addition.
- Test Example 2 The stability test of the test compound in human liver microsomes (Ms) was performed according to the following method. The test compound was added with 0.1 M phosphoric acid together with human liver microsome fraction (Xenotech / H630B / lot.0810472) in the presence of NADPH production system (0.16 mM NADP +, 2.5 mM MgCl2, 1.5 mM glucose-6-phosphate). Incubated in buffer (pH 7.4) (37 ° C., 15 minutes). The final concentrations of the test compound and liver Ms protein were 1 ⁇ M and 0.25 mg protein / mL, respectively.
- the reaction mixture after the incubation was added with 2 volumes of DMSO, stirred, and then centrifuged at 2150 ⁇ g (4 ° C., 10 minutes).
- the obtained supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS / MS) system.
- the lower limit of quantification was 0.1 ⁇ M.
- the metabolic rate of the compound of Example 1 was 27.8%.
- the compound of the present invention was shown to have an OX receptor antagonistic action. Therefore, the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease modulated by OX receptor antagonism, such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease , Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc. .
- OX receptor antagonism such as sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, Alzheimer's disease , Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, hypertension, etc.
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Abstract
Description
OX受容体のサブタイプによって組織分布は異なっており、OX1受容体はノルアドレナリン作動性神経の起始核である青斑核、OX2受容体はヒスタミン神経の起始核である結節乳頭核に高密度に発現している(非特許文献3、非特許文献4及び非特許文献5参照)。セロトニン神経の起始核である縫線核や、ドパミン神経の起始核である腹側被蓋野にはOX1受容体とOX2受容体両方の発現がみられる(非特許文献3参照)。オレキシン神経は脳幹と視床下部のモノアミン神経系に投射し、それらの神経に対して興奮性の影響を与えており、さらにREM睡眠の制御に関わる脳幹のアセチルコリン神経にもOX2受容体の発現がみられ、これらの神経核の活性にも影響を及ぼしている(非特許文献3及び非特許文献4参照)。 Both OX-A and OX-B act on the OX receptor. The OX receptor has been previously cloned into two subtypes of OX1 and OX2 receptors, and both are known to be 7-transmembrane G protein-coupled receptors that are mainly expressed in the brain. . The OX1 receptor is specifically conjugated to Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).
The tissue distribution varies depending on the subtype of the OX receptor. The OX1 receptor is dense in the locus coeruleus, the origin of noradrenergic nerves, and the OX2 receptor in the nodule papillary nucleus, the origin of histamine neurons. (See Non-Patent Document 3, Non-Patent Document 4 and Non-Patent Document 5). Expression of both the OX1 receptor and the OX2 receptor is observed in the raphe nucleus which is the origin nucleus of the serotonin nerve and the ventral tegmental area which is the origin nucleus of the dopamine nerve (see Non-Patent Document 3). The orexin nerve projects to the brain stem and the monoamine nervous system of the hypothalamus and exerts an excitatory effect on those nerves. Furthermore, the expression of OX2 receptor is also seen in the acetylcholine nerve of the brain stem involved in REM sleep control. It also affects the activity of these nerve nuclei (see Non-Patent Document 3 and Non-Patent Document 4).
OX受容体拮抗作用化合物としては、例えば総説として非特許文献11に記載の種々の構造を有する化合物が知られている。また、特許文献1~3には、置換ピペリジン誘導体が開示されているが、本願記載のピペリジン環にベンゾオキサゾール環が直接結合している化合物についての開示はない。 In recent years, attention has been focused on the relationship between OX1 and OX2 receptors and sleep / wake regulation, and the usefulness of compounds having OX receptor antagonistic activity has been studied. When OX-A is administered into the cerebral ventricles of rats, the amount of spontaneous movement is increased (see Non-Patent Document 6 and Non-Patent Document 7), the behavior is increased (see Non-Patent Document 7), and the awakening time is extended (Non-Patent Document). 6). The effect of shortening REM sleep time by administration of OX-A is completely antagonized by pretreatment with an OX receptor antagonist (see Non-Patent Document 8). In addition, administration of substances that antagonize OX1 and OX2 receptors to the same extent that can be administered orally has been reported to reduce exercise, shorten sleep onset latency, increase non-REM sleep and REM sleep (non-) (See Patent Document 9 and Non-Patent Document 10).
As OX receptor antagonistic compounds, for example, compounds having various structures described in Non-Patent Document 11 as a review are known. Patent Documents 1 to 3 disclose substituted piperidine derivatives, but do not disclose a compound in which a benzoxazole ring is directly bonded to the piperidine ring described in the present application.
以下、本発明を詳細に説明する。本発明の態様(以下、「本発明化合物」という)は以下に示すものである。
(1)式(IA)
Xは、窒素原子、又は式CHを示し、
Yは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基(該C1-6アルキル基は、1~3個のハロゲン原子で置換されてもよい)、又はC1-6アルコキシ基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1~3個の置換基で置換されてもよい)を示し、
R3及びR4は、同一に又は異なって、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1~3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩、
(2)上記式(IA)において、
R3が、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1~3個のハロゲン原子で置換されてもよい)であり、
R4が、水素原子、又はハロゲン原子である(1)に記載のメチルピペリジン誘導体、又はその医薬上許容される塩、
(3)上記式(IA)において、
R2が、トリアゾリル基、又はピリミジニル基(該ピリミジニル基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1~3個の置換基で置換されてもよい)である(1)又は(2)いずれかに記載のメチルピペリジン誘導体、又はその医薬上許容される塩、
(4)上記式(IA)において、
R1が、水素原子、ハロゲン原子、又はC1-6アルキル基である(1)~(3)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩、
(5)上記式(IA)において、
Yが、式CHであり、
R2が、トリアゾリル基、又はピリミジニル基である(1)~(4)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩、
(6)上記式(IA)において、
Xが、窒素原子であり、
R4が、水素原子である(1)~(5)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩、
(7)上記式(IA)が、式(IIA)
(8)式(I)
Xは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、又はC1-6アルキル基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、1~3個のハロゲン原子で置換されてもよい)を示し、
R3は、水素原子、ハロゲン原子、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1~3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩、
(9)上記式(I)において、
Xが、窒素原子であり、
R1が、水素原子、又はC1-6アルキル基であり、
R2が、トリアゾリル基、又はピリミジニル基であり、
R3が、ハロゲン原子である(8)に記載のメチルピペリジン誘導体、又はその医薬上許容される塩、
(10)上記式(I)が、式(II)
(11)上記(1)~(10)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有する医薬、
(12)上記(1)~(10)いずれか1つに記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有する睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、頭痛、片頭痛、疼痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、又は高血圧等の疾患の治療又は予防薬。 As a result of intensive studies on a novel skeletal compound having an antagonistic action on the orexin receptor, the present inventors have found that a certain methylpiperidine derivative represented by the following formula has an excellent OX receptor antagonistic action. The present invention has been completed.
Hereinafter, the present invention will be described in detail. The embodiment of the present invention (hereinafter referred to as “the compound of the present invention”) is shown below.
(1) Formula (IA)
X represents a nitrogen atom or the formula CH;
Y represents a nitrogen atom or the formula CH;
R 1 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms), or C 1-6 alkoxy Group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group);
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and C 1-6 The alkoxy group may be substituted with 1 to 3 halogen atoms). )
A methylpiperidine derivative represented by: or a pharmaceutically acceptable salt thereof,
(2) In the above formula (IA),
R 3 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be)
The methylpiperidine derivative according to (1), wherein R 4 is a hydrogen atom or a halogen atom, or a pharmaceutically acceptable salt thereof,
(3) In the above formula (IA),
R 2 is a triazolyl group or a pyrimidinyl group (the pyrimidinyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). A certain methylpiperidine derivative according to (1) or (2), or a pharmaceutically acceptable salt thereof,
(4) In the above formula (IA),
(1) to (3) the methylpiperidine derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (3), wherein R 1 is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group;
(5) In the above formula (IA),
Y is the formula CH;
(2) The methylpiperidine derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (4), wherein R 2 is a triazolyl group or a pyrimidinyl group,
(6) In the above formula (IA),
X is a nitrogen atom,
The methylpiperidine derivative or a pharmaceutically acceptable salt thereof according to any one of (1) to (5), wherein R 4 is a hydrogen atom;
(7) The above formula (IA) is converted to formula (IIA)
(8) Formula (I)
X represents a nitrogen atom or the formula CH;
R 1 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with 1 to 3 halogen atoms);
R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be). )
A methylpiperidine derivative represented by: or a pharmaceutically acceptable salt thereof,
(9) In the above formula (I),
X is a nitrogen atom,
R 1 is a hydrogen atom or a C 1-6 alkyl group,
R 2 is a triazolyl group or a pyrimidinyl group;
The methylpiperidine derivative according to (8), or a pharmaceutically acceptable salt thereof, wherein R 3 is a halogen atom;
(10) The above formula (I) is converted to formula (II)
(11) A drug containing the methylpiperidine derivative according to any one of (1) to (10) above, or a pharmaceutically acceptable salt thereof as an active ingredient,
(12) Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia containing the methylpiperidine derivative according to any one of (1) to (10) above or a pharmaceutically acceptable salt thereof as an active ingredient Treatment of diseases such as infectious diseases, drug addiction, Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune related diseases, endocrine related diseases, or hypertension Or prophylactic drugs.
「ハロゲン原子」とは、フッ素原子、塩素原子、臭素原子、ヨウ素原子である。
「C1-6アルキル基」とは直鎖状又は分岐鎖状の炭素数1~6個のアルキル基を意味し、例えばメチル、エチル、n-プロピル、イソプロピル、n-ブチル、イソブチル、sec-ブチル、tert-ブチル、n-ペンチル、イソペンチル、ネオペンチル、tert-ペンチル、1-エチルプロピル、n-ヘキシル、イソヘキシル、ネオヘキシル基等を挙げることができる。
「C1-6アルコキシ基」とは直鎖状又は分岐鎖状の炭素数1~6個のアルコキシ基を意味し、例えばメトキシ、エトキシ、n-プロポキシ、イソプロポキシ、n-ブトキシ、イソブトキシ、sec-ブトキシ、tert-ブトキシ、n-ペンチルオキシ、イソペンチルオキシ、ネオペンチルオキシ、tert-ペンチルオキシ、1-エチルプロポキシ、n-ヘキシルオキシ基等を挙げることができる。
「ヘテロアリール」とは窒素原子、酸素原子及び硫黄原子からなる群より選ばれる同一又は異なる1個以上の複素原子と1~5個の炭素原子からなる5員又は6員のヘテロアリールを意味し、例えばピラゾリル、イミダゾリル、トリアゾリル、オキサゾリル、チアゾリル、ピリジル、ピラジニル、ピリミジニル、ピリダジニル基等を挙げることができる。 The terms used in the present specification have the following meanings.
The “halogen atom” is a fluorine atom, a chlorine atom, a bromine atom, or an iodine atom.
“C 1-6 alkyl group” means a linear or branched alkyl group having 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec- Examples thereof include butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group and the like.
“C 1-6 alkoxy group” means a linear or branched alkoxy group having 1 to 6 carbon atoms, such as methoxy, ethoxy, n-propoxy, isopropoxy, n-butoxy, isobutoxy, sec -Butoxy, tert-butoxy, n-pentyloxy, isopentyloxy, neopentyloxy, tert-pentyloxy, 1-ethylpropoxy, n-hexyloxy group and the like can be mentioned.
“Heteroaryl” means a 5- or 6-membered heteroaryl consisting of one or more heteroatoms selected from the group consisting of a nitrogen atom, an oxygen atom and a sulfur atom, and 1 to 5 carbon atoms. Examples thereof include pyrazolyl, imidazolyl, triazolyl, oxazolyl, thiazolyl, pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl group and the like.
Yは、式CHである化合物が好ましい。
Xは、窒素原子である化合物が好ましい。
R1は、水素原子、ハロゲン原子(ただし、ヨウ素原子を除く)、又はC1-6アルキル基である化合物が好ましく、ここでハロゲン原子はフッ素原子である化合物がより好ましく、C1-6アルキル基はメチル基である化合物がより好ましい。
R2は、トリアゾリル基、又はピリミジニル基である化合物が好ましく、1,2,3-トリアゾール-2-イル基、又はピリミジン-2-イル基である化合物がより好ましい。
R3は、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1~3個のハロゲン原子で置換されてもよい)である化合物が好ましく、ハロゲン原子、又はC1-6アルキル基(該C1-6アルキル基は1~3個のフッ素原子で置換されている)である化合物がより好ましく、フッ素原子、塩素原子、又はトリフルオロメチル基である化合物がさらに好ましく、フッ素原子、又は塩素原子である化合物が特に好ましい。
R4は、水素原子、又はハロゲン原子である化合物が好ましく、水素原子、又はフッ素原子である化合物がより好ましい。
本発明化合物中の好ましい化合物の例として、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][6-メチル-3-(2H-1,2,3-トリアゾール-2-イル)ピリジン-2-イル]メタノン、
[(2R*,5R*)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][6-メチル-3-(ピリミジン-2-イル)ピリジン-2-イル]メタノン、
[(2R*,5R*)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R*,5R*)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][6-メチル-3-(2H-1,2,3-トリアゾール-2-イル)ピリジン-2-イル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-クロロ-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][3-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][4-フルオロ-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-フルオロ-6-(ピリミジン-2-イル)フェニル]メタノン、
[5-ブロモ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル][(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(5-メトキシピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][4-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[5-クロロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル][(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル]メタノン、
[(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(ピリミジン-2-イル)フェニル]メタノン、
[5-クロロ-2-(ピリミジン-2-イル)フェニル][(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル]メタノン、
[(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]{(2R,5R)-2-メチル-5-[5-(トリフルオロメチル)-1,3-ベンゾオキサゾール-2-イル]ピペリジン-1-イル}メタノン、
[5-メチル-2-(ピリミジン-2-イル)フェニル]{(2R,5R)-2-メチル-5-[5-(トリフルオロメチル)-1,3-ベンゾオキサゾール-2-イル]ピペリジン-1-イル}メタノン、
[5-クロロ-2-(ピリミジン-2-イル)フェニル]{(2R,5R)-2-メチル-5-[5-(トリフルオロメチル)-1,3-ベンゾオキサゾール-2-イル]ピペリジン-1-イル}メタノン、
[(2R,5R)-5-(6-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(6-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(6-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(6-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][6-メチル-3-(2H-1,2,3-トリアゾール-2-イル)ピリジン-2-イル]メタノン、
[(2R,5R)-5-(6-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(6-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][2-フルオロ-6-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン
、
[(2R,5R)-5-(5,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(ピリミジン-2-イル)フェニル]メタノン、
[5-クロロ-2-(ピリミジン-2-イル)フェニル][(2R,5R)-5-(5,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル]メタノン、
[(2R,5R)-5-(5,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][6-メチル-3-(2H-1,2,3-トリアゾール-2-イル)ピリジン-2-イル]メタノン、
[(2R,5R)-5-(5,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
2-{(3R,6R)-6-メチル-1-[5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)ベンゾイル]ピペリジン-3-イル}-1,3-ベンゾオキサゾール-5-カルボニトリル、
2-{(3R,6R)-6-メチル-1-[5-メチル-2-(ピリミジン-2-イル)ベンゾイル]ピペリジン-3-イル}-1,3-ベンゾオキサゾール-5-カルボニトリル、
[(2R,5R)-5-(6,7-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(6,7-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(4,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(4,6-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5,7-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(5,7-ジフルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(7-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(4-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(4-フルオロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(4-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
[(2R,5R)-5-(4-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(4-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][5-フルオロ-2-(ピリミジン-2-イル)フェニル]メタノン、
[(2R,5R)-5-(6-クロロ[1,3]オキサゾロ[5,4-b]ピリジン-2-イル)-2-メチルピペリジン-1-イル][5-メチル-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、及び
[(2R,5R)-5-(6-クロロ[1,3]オキサゾロ[5,4-b]ピリジン-2-イル)-2-メチルピペリジン-1-イル][4-フルオロ-2-(2H-1,2,3-トリアゾール-2-イル)フェニル]メタノン、
が挙げられる。
なお、本発明化合物が水和物又は溶媒和物を形成する場合、それらも本発明の範囲内に含まれる。同様に、本発明化合物の水和物又は溶媒和物の医薬上許容される塩も本発明の範囲内に含まれる。 Preferred embodiments of the compound of the present invention are listed below.
Y is preferably a compound of formula CH.
A compound in which X is a nitrogen atom is preferable.
R 1 is preferably a hydrogen atom, a halogen atom (excluding an iodine atom), or a C 1-6 alkyl group, wherein the halogen atom is more preferably a fluorine atom, and a C 1-6 alkyl group. More preferably, the group is a methyl group.
R 2 is preferably a compound that is a triazolyl group or a pyrimidinyl group, and more preferably a compound that is a 1,2,3-triazol-2-yl group or a pyrimidin-2-yl group.
R 3 represents a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms). And a compound that is a halogen atom or a C 1-6 alkyl group (the C 1-6 alkyl group is substituted with 1 to 3 fluorine atoms) is more preferable, A compound which is a fluorine atom, a chlorine atom or a trifluoromethyl group is more preferred, and a compound which is a fluorine atom or a chlorine atom is particularly preferred.
R 4 is preferably a compound that is a hydrogen atom or a halogen atom, and more preferably a compound that is a hydrogen atom or a fluorine atom.
Examples of preferred compounds in the compounds of the present invention include
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazole -2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (pyrimidin-2-yl ) Pyridin-2-yl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone ,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R *, 5R *)-5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R *, 5R *)-5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-chloro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [3-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (5-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Bromo-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (5-methoxypyrimidine-2- Yl) phenyl] methanone,
[(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (2H-1,2,3-triazole-2 -Yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Chloro-2- (2H-1,2,3-triazol-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl)- 2-methylpiperidin-1-yl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2- (pyrimidin-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl ] Methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[5-Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3- Benzoxazol-2-yl] piperidin-1-yl} methanone,
[5-Methyl-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] {(2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzoxazol-2-yl] piperidine -1-yl} methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzooxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3 -Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (6-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [2-fluoro-6- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl ) Phenyl] methanone,
[5-Chloro-2- (pyrimidin-2-yl) phenyl] [(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1 -Il] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [6-methyl-3- (2H-1,2, , 3-Triazol-2-yl) pyridin-2-yl] methanone,
[(2R, 5R) -5- (5,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidin-3-yl} -1,3- Benzoxazole-5-carbonitrile,
2-{(3R, 6R) -6-methyl-1- [5-methyl-2- (pyrimidin-2-yl) benzoyl] piperidin-3-yl} -1,3-benzoxazole-5-carbonitrile,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (6,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4,6-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2, , 3-Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (5,7-difluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) ) Phenyl] methanone,
[(2R, 5R) -5- (7-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (4-Chloro-1,3-benzoxazol-2-yl) -2-methylpiperidin-1-yl] [5-fluoro-2- (pyrimidin-2-yl) phenyl ] Methanone,
[(2R, 5R) -5- (6-Chloro [1,3] oxazolo [5,4-b] pyridin-2-yl) -2-methylpiperidin-1-yl] [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) phenyl] methanone and [(2R, 5R) -5- (6-chloro [1,3] oxazolo [5,4-b] pyridin-2-yl ) -2-methylpiperidin-1-yl] [4-fluoro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
Is mentioned.
In addition, when this invention compound forms a hydrate or a solvate, they are also contained in the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.
本発明に係る化合物には、一つ以上の水素原子、炭素原子、窒素原子、酸素原子、フッ素原子が放射性同位元素や安定同位元素と置換された化合物も含まれる。これらの標識化合物は、代謝や薬物動態研究、受容体のリガンド等として生物学的分析等に有用である。
本発明に係る化合物は、経口又は非経口的に投与することができる。その投与剤型は錠剤、カプセル剤、顆粒剤、散剤、粉剤、トローチ剤、軟膏剤、クリーム剤、皮膚貼付剤、乳剤、懸濁剤、坐剤、注射剤等であり、いずれも慣用の製剤技術(例えば、第15改正日本薬局方に規定する方法等)によって製造することができる。これらの投与剤型は、患者の症状、年齢、体重、及び治療の目的に応じて適宜選択することができる。
これらの製剤は、本発明の化合物を含有する組成物に薬理学的に許容されるキャリヤー、すなわち、賦形剤(例えば、結晶セルロース、デンプン、乳糖、マンニトール)、結合剤(例えば、ヒドロキシプロピルセルロース、ポリビニルピロリドン)、滑沢剤(例えば、ステアリン酸マグネシウム、タルク)、崩壊剤(例えば、カルボキシメチルセルロースカルシウム)、その他薬理学的に許容される各種添加剤を配合し、製造することができる。
本発明の化合物は、成人患者に対して1回の投与量として0.001~500mgを1日1回又は数回に分けて経口又は非経口で投与することが可能である。なお、この投与量は治療対象となる疾病の種類、患者の年齢、体重、症状等により適宜増減することができる。 The compounds of the present invention include all enantiomers, diastereomers, equilibrium compounds, mixtures of these in any proportion, racemates and the like.
The compounds according to the present invention also include compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms and fluorine atoms are substituted with radioactive isotopes or stable isotopes. These labeled compounds are useful for metabolic and pharmacokinetic studies, biological ligands, etc. as receptor ligands.
The compound according to the present invention can be administered orally or parenterally. The dosage forms are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin patches, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulations It can be manufactured by technology (for example, the method prescribed in the 15th revision Japanese Pharmacopoeia). These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.
These formulations are pharmaceutically acceptable carriers for the compositions containing the compounds of the invention, ie excipients (eg crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose). , Polyvinylpyrrolidone), lubricants (for example, magnesium stearate, talc), disintegrants (for example, carboxymethyl cellulose calcium), and other various pharmacologically acceptable additives.
The compound of the present invention can be orally or parenterally administered to an adult patient at a dosage of 0.001 to 500 mg once or several times a day. The dose can be appropriately increased or decreased depending on the type of disease to be treated, the age, weight, symptoms, etc. of the patient.
本発明の化合物(IA)の代表的な製造法を以下のスキームA~Cに示す。以下の方法は、本発明化合物の製造法の例示であり、これに限定されるものではない。なお、以下の製造法の例示において、化合物は反応に支障にならない塩を形成していてもよい。
スキームA Desirable profiles in the compounds of the present invention include excellent drug efficacy, excellent pharmacokinetics (eg, good oral absorption), excellent physical properties, low toxicity, and the like. .
Representative schemes for producing the compound (IA) of the present invention are shown in the following schemes AC. The following method is an illustration of the production method of the compound of the present invention, and is not limited thereto. In the following examples of production methods, the compound may form a salt that does not hinder the reaction.
Scheme A
工程A-2:化合物(4)は、化合物(2)と化合物(3)との縮合反応により得ることができる。工程A-2の縮合反応には、脱水縮合剤を用いた方法等が挙げられる。脱水縮合剤には、DMT-MM(4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド)、1-エチル-3-(3-ジメチルアミノプロピル)カルボジイミド・塩酸塩、プロパンホスホニックアシッドアンハイドライド、HATU[O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロホスファート]、TBTU(O-(ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム テトラフルオロボレート)、ジシクロヘキシルカルボジイミド、ジフェニルホスホニルアジド、カルボニルジイミダゾール等が挙げられ、必要に応じて1-ヒドロキシベンゾトリアゾール、ヒドロキシスクシンイミド等の活性化剤を用いることができる。反応溶媒としては、N,N-ジメチルホルムアミド、テトラヒドロフラン、ジクロロメタン、クロロホルム、トルエン、酢酸エチル、メタノール、エタノール、水等や、それらの混合溶媒が挙げられる。この際、塩基を用いて行うことができ、塩基の例としては、ピリジン、トリエチルアミン、ジイソプロピルエチルアミン等の有機アミン類、炭酸カリウム等の無機塩基等が挙げられる。反応は0℃~還流温度で行うことができる。
工程A-3:化合物(5)は、化合物(4)から閉環反応により得ることができる。工程A-3における反応は、無溶媒下、若しくはアセトニトリル、テトラヒドロフラン、クロロホルム等の溶媒中、又はそれらの混合溶媒中、塩化チオニル、オキシ塩化リン、ポリリン酸、酢酸、トリフェニルホスフィン/DEAD(ジエチルアゾジカルボキシラート)、トリフェニルホスフィン/ヘキサクロロエタン等を使用し、0℃~還流温度条件下で行うことができる。
工程A-4:化合物(6)は、化合物(5)を、塩酸、硫酸、トリフルオロ酢酸、p-トルエンスルホン酸、メタンスルホン酸等の酸と反応させることにより得ることができる。工程A-4における反応に関する包括的概観は、J. F. W. McOmie 著、Protective Groups in Organic Chemistry、及びT. W. Greene 及びP.G.M.Wuts著、Protective Groups in Organic Synthesisに見出され得る。
工程A-5:化合物(8)は、化合物(6)と化合物(7)との縮合反応により得ることができる。工程A-5の縮合反応は、工程A-2と同様の反応条件に従って行うことができる。
スキームB Step A-1: Compound (2) can be obtained by hydrolysis reaction of ester of compound (1). The reaction in Step A-1 uses an aqueous solution of lithium hydroxide, sodium hydroxide, potassium hydroxide or the like as a base, and uses methanol, ethanol, tetrahydrofuran or the like as a mixed solvent for increasing the solubility of the substrate or adjusting the reaction temperature. You can also This reaction can be performed under conditions of 0 ° C. to reflux temperature.
Step A-2: The compound (4) can be obtained by a condensation reaction of the compound (2) and the compound (3). Examples of the condensation reaction in Step A-2 include a method using a dehydrating condensing agent. Examples of the dehydrating condensing agent include DMT-MM (4- (4,6-dimethoxy-1,3,5-triazin-2-yl) -4-methylmorpholinium chloride), 1-ethyl-3- (3- Dimethylaminopropyl) carbodiimide / hydrochloride, propanephosphonic acid anhydride, HATU [O- (7-azabenzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate TBTU (O- (benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium tetrafluoroborate), dicyclohexylcarbodiimide, diphenylphosphonyl azide, carbonyldiimidazole, etc. Activating agents such as 1-hydroxybenzotriazole and hydroxysuccinimide are added as necessary. It is possible to have. Examples of the reaction solvent include N, N-dimethylformamide, tetrahydrofuran, dichloromethane, chloroform, toluene, ethyl acetate, methanol, ethanol, water, and a mixed solvent thereof. In this case, the reaction can be carried out using a base. Examples of the base include organic amines such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate. The reaction can be carried out at 0 ° C. to reflux temperature.
Step A-3: Compound (5) can be obtained from compound (4) by a ring-closing reaction. The reaction in Step A-3 is carried out in the absence of a solvent, in a solvent such as acetonitrile, tetrahydrofuran, chloroform, or a mixed solvent thereof, thionyl chloride, phosphorus oxychloride, polyphosphoric acid, acetic acid, triphenylphosphine / DEAD (diethylazo Dicarboxylate), triphenylphosphine / hexachloroethane, etc. can be used and the reaction can be carried out at 0 ° C. to reflux temperature.
Step A-4: Compound (6) can be obtained by reacting compound (5) with an acid such as hydrochloric acid, sulfuric acid, trifluoroacetic acid, p-toluenesulfonic acid, methanesulfonic acid and the like. A comprehensive overview of the reaction in step A-4 can be found in F. W. McOmie, Protective Groups in Organic Chemistry, and T. W. Greene and P.A. G. M. Can be found in Wuts, Protective Groups in Organic Synthesis.
Step A-5: Compound (8) can be obtained by a condensation reaction of compound (6) and compound (7). The condensation reaction in step A-5 can be carried out according to the same reaction conditions as in step A-2.
Scheme B
工程B-1:化合物(10)は、化合物(9)と化合物(7)との縮合反応より得ることができる。工程B-1の縮合反応は工程A-2と同様の反応条件に従って行うことができる。
工程B-2:化合物(11)は、化合物(10)のエステルの加水分解反応により得ることができる。工程B-2の反応は工程A-1と同様の反応条件に従って行うことができる。又は塩酸、硫酸等の鉱酸の水溶液を用いた酸加水分解によっても得ることができる。溶媒はメタノール、エタノール、1,4‐ジオキサン等を混合溶媒として使用することができる。本反応は、0℃~還流温度の条件下にて行うことができる。
工程B-3:化合物(12)は、化合物(11)と化合物(3’)との縮合反応により得ることができる。工程B-3の縮合反応は工程A-2と同様の反応条件に従って行うことができる。
工程B-4:化合物(13)は、化合物(12)の閉環反応により得ることができる。工程B-4における反応は工程A-3と同様の反応条件に従って行うことができる。
スキームC
Step B-1: The compound (10) can be obtained by a condensation reaction of the compound (9) and the compound (7). The condensation reaction in step B-1 can be carried out according to the same reaction conditions as in step A-2.
Step B-2: Compound (11) can be obtained by hydrolysis reaction of ester of compound (10). The reaction in Step B-2 can be performed according to the same reaction conditions as in Step A-1. Alternatively, it can also be obtained by acid hydrolysis using an aqueous solution of a mineral acid such as hydrochloric acid or sulfuric acid. As the solvent, methanol, ethanol, 1,4-dioxane and the like can be used as a mixed solvent. This reaction can be performed under conditions of 0 ° C. to reflux temperature.
Step B-3: Compound (12) can be obtained by a condensation reaction of compound (11) and compound (3 ′). The condensation reaction in Step B-3 can be performed according to the same reaction conditions as in Step A-2.
Step B-4: Compound (13) can be obtained by ring-closing reaction of compound (12). The reaction in Step B-4 can be performed according to the same reaction conditions as in Step A-3.
Scheme C
工程C-1:化合物(14)は、化合物(2)と化合物(3’)との環化反応により得ることができる。工程C-1における反応は、酸触媒としてEaton試薬を用い、80~120℃の条件下にて行うことができる。
工程C-2:化合物(15)は、化合物(14)と化合物(7)との縮合反応より得ることができる。工程C-2の縮合反応は工程A-2と同様の反応条件に従って行うことができる。
Step C-1: Compound (14) can be obtained by cyclization reaction of Compound (2) and Compound (3 ′). The reaction in Step C-1 can be performed under conditions of 80 to 120 ° C. using an Eaton reagent as an acid catalyst.
Step C-2: The compound (15) can be obtained by a condensation reaction of the compound (14) and the compound (7). The condensation reaction in Step C-2 can be performed according to the same reaction conditions as in Step A-2.
以下の参考例及び実施例においてカラムクロマトグラフィーを使用して精製した際の「KP-Sil」にはBiotage社SNAPCartridge KP-Sil、「HP-Sil」にはBiotage社SNAPCartridge HP-Sil、「KP-NH」にはBiotage社SNAPCartridge KP-NHを使用した。 Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples. However, the present invention is not limited to these examples, and may be changed without departing from the scope of the present invention.
In the following Reference Examples and Examples, “KP-Sil” when purified using column chromatography is Biotage's SNAP Cartridge KP-Sil, “HP-Sil” is Biotage's SNAP Cartridge HP-Sil, “KP-Sil.” For NH, Biotage SNAP Cartridge KP-NH was used.
機械:Gilson社 preparative HPLC system
カラム:資生堂 Capcelpak C18 MGII 5μm 20×150mm
溶媒:A液;0.1%トリフルオロ酢酸含有水、B液;0.1%トリフルオロ酢酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、22分(A液/B液=20/80)、25分(A液/B液=10/90)
流速:20mL/min、検出法:UV 254nm In the following Reference Examples and Examples, purification by preparative high performance liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation for obtaining a free form may be performed.
Machine: Gilson preparative HPLC system
Column: Shiseido Capcelpak C18 MGII 5 μm 20 × 150 mm
Solvent: A solution; 0.1% trifluoroacetic acid-containing water, B solution; 0.1% trifluoroacetic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 22 minutes (A solution / B Liquid = 20/80), 25 minutes (A liquid / B liquid = 10/90)
Flow rate: 20 mL / min, detection method: UV 254 nm
・条件1
測定機械:MicroMass社 Platform LCおよびAgilent社 Agilent1100
カラム:Waters社 SunFire C18 2.5μm4.6x50mm
溶媒:0.1%トリフルオロ酢酸含有水、B液;0.1%トリフルオロ酢酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、0.5分(A液/B液=90/10)、5.5分(A液/B液=20/80)、6.0分(A液/B液=1/99)、6.3分(A液/B液=1/99)
流速:1mL/min、検出法:254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)
・条件2
測定機械:SHIMADZU社 LCMS-2010EV
カラム:SHIMADZU社 Shimpack XR-ODS 2.2μm 2.0x30mm
溶媒:A液0.1%ギ酸含有水、B液;0.1%ギ酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、1分(A液/B液=60/40)、2分(A液/B液=0/100)、2.5分(A液/B液=0/100)
流速:0.6mL/min、検出法:254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)及び大気圧化学イオン法(APCI:Atomospheric Pressure Chemical Ionization)
・条件3
測定機械:SHIMADZU社 LCMS-2010EV
カラム:SHIMADZU社 Shimpack XR-ODS 2.2μm 2.0x30mm
溶媒:A液0.1%ギ酸含有水、B液;0.1%ギ酸含有アセトニトリル
グラジエント:0分(A液/B液=90/10)、3分(A液/B液=60/40)、5.5分(A液/B液=0/100)、6.5分(A液/B液=0/100)
流速:0.6mL/min、検出法:254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)及び大気圧化学イオン法(APCI:Atomospheric Pressure Chemical Ionization)
・条件4
測定機械:Agilent社 Agilent2900及びAgilent6150
カラム:Waters社 Acquity CSH C18 1.7μm 2.1x50mm
溶媒:A液;0.1%ギ酸含有水、B液;0.1%ギ酸含有アセトニトリル
グラジエント:0分(A液/B液=80/20)、1.2~1.4分(A液/B液=1/99)
流速:0.8mL/min、検出法:UV 254nm
イオン化法:エレクトロンスプレー法(ESI:Electron Spray Ionization)
以下の実施例において、ラセミ体の分割は以下の3種類の条件のいずれかにより実施した。
・条件1
カラム:CHIRALPAK AD(ダイセル化学工業)、20mm×250mm
移動相:ヘキサン/エタノール=40/60(v/v)
流速:5.0mL/min
・条件2
カラム:CHIRALPAK AD(ダイセル化学工業)、20mm×250mm
移動相:ヘキサン/エタノール=80/20(v/v)~0/100(v/v)
流速:5.0mL/min
・条件3
カラム:CHIRALPAK IC(ダイセル化学工業)、10cm×25cm
移動相:ヘキサン/2-プロパノール=90/10(v/v)
流速:142mL/min.
以下の実施例において、キラル分析は以下条件により実施した。
・条件A
カラム:CHIRALPAK AD-H(ダイセル)、4.6mm×250mm
流速:1.0mL/min
移動相:ヘキサン/エタノール=50/50 In the following Reference Examples and Examples, high performance liquid chromatography mass spectrum (LCMS) was measured under any of the following four conditions.
・ Condition 1
Measuring machine: Micromass Platform LC and Agilent Agilent 1100
Column: Waters SunFire C18 2.5 μm 4.6 × 50 mm
Solvent: water containing 0.1% trifluoroacetic acid, liquid B; acetonitrile gradient containing 0.1% trifluoroacetic acid: 0 minutes (liquid A / liquid B = 90/10), 0.5 minutes (liquid A / liquid B) = 90/10), 5.5 minutes (A liquid / B liquid = 20/80), 6.0 minutes (A liquid / B liquid = 1/99), 6.3 minutes (A liquid / B liquid = 1) / 99)
Flow rate: 1 mL / min, detection method: 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)
・ Condition 2
Measuring machine: SHIMADZU LCMS-2010EV
Column: SHIMADZU Shimpack XR-ODS 2.2 μm 2.0 × 30 mm
Solvent: A solution 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 1 minute (A solution / B solution = 60/40) ) 2 minutes (A liquid / B liquid = 0/100), 2.5 minutes (A liquid / B liquid = 0/100)
Flow rate: 0.6 mL / min, detection method: 254 nm
Ionization method: Electron Spray Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI)
・ Condition 3
Measuring machine: SHIMADZU LCMS-2010EV
Column: SHIMADZU Shimpack XR-ODS 2.2 μm 2.0 × 30 mm
Solvent: A solution 0.1% formic acid-containing water, B solution; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (A solution / B solution = 90/10), 3 minutes (A solution / B solution = 60/40) ) 5.5 minutes (A liquid / B liquid = 0/100), 6.5 minutes (A liquid / B liquid = 0/100)
Flow rate: 0.6 mL / min, detection method: 254 nm
Ionization method: Electron Spray Ionization (ESI) and Atmospheric Pressure Chemical Ionization (APCI)
・ Condition 4
Measuring machine: Agilent Agilent 2900 and Agilent 6150
Column: Waters Acquity CSH C18 1.7 μm 2.1 × 50 mm
Solvent: solution A; 0.1% formic acid-containing water, solution B; 0.1% formic acid-containing acetonitrile gradient: 0 minutes (solution A / solution B = 80/20), 1.2 to 1.4 minutes (solution A) / B liquid = 1/99)
Flow rate: 0.8 mL / min, detection method: UV 254 nm
Ionization method: Electron Spray Ionization (ESI: Electron Spray Ionization)
In the following examples, racemic resolution was performed under any of the following three conditions.
・ Condition 1
Column: CHIRALPAK AD (Daicel Chemical Industries), 20 mm x 250 mm
Mobile phase: hexane / ethanol = 40/60 (v / v)
Flow rate: 5.0 mL / min
・ Condition 2
Column: CHIRALPAK AD (Daicel Chemical Industries), 20 mm x 250 mm
Mobile phase: hexane / ethanol = 80/20 (v / v) to 0/100 (v / v)
Flow rate: 5.0 mL / min
・ Condition 3
Column: CHIRALPAK IC (Daicel Chemical Industries), 10cm x 25cm
Mobile phase: hexane / 2-propanol = 90/10 (v / v)
Flow rate: 142 mL / min.
In the following examples, chiral analysis was performed under the following conditions.
・ Condition A
Column: CHIRALPAK AD-H (Daicel), 4.6 mm x 250 mm
Flow rate: 1.0 mL / min
Mobile phase: hexane / ethanol = 50/50
MS測定機器:SHIMADZU社LCMS-2010EVあるいはmicromass社 Platform LC
以下の参考例および実施例において、化合物名はACD/Name (ACD/Labs 12.01, Advanced Chemistry Development Inc.)により命名した。 In the following Reference Examples and Examples, mass spectra (MS) were measured under the following conditions.
MS measuring instrument: SHIMADZU LCMS-2010EV or micromass Platform LC
In the following Reference Examples and Examples, compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).
Na2SO4(無水硫酸ナトリウム)、MgSO4(無水硫酸マグネシウム)、Na2CO3(炭酸ナトリウム)、Cs2CO3(炭酸セシウム)、NaHCO3(炭酸水素ナトリウム)、NaOH(水酸化ナトリウム)、LiOH・H2O(水酸化リチウム・一水和物)、MeOH(メタノール)、EtOH(エタノール)、Et2O(ジエチルエーテル)、THF(テトラヒドロフラン)、DMF(N,N-ジメチルホルムアミド)、MeCN(アセトニトリル)、EtOAc(酢酸エチル)、CHCl3(クロロホルム)、HOBt・H2O(1-ヒドロキシベンゾトリアゾール・一水和物)、EDC・HCl[1-(3-ジメチルアミノプロピル)-3-エチルカルボジイミド・一塩酸塩]、HATU[O-(7-アザベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム ヘキサフルオロホスファート]、DMT-MM(4-(4,6-ジメトキシ-1,3,5-トリアジン-2-イル)-4-メチルモルホリニウムクロリド)、Pd(PPh3)4[テトラキストリフェニルホスフィンパラジウム(0)]、brine(飽和食塩水)、Boc(tert-ブトキシカルボニル)、THP(テトラヒドロピラニル)、DIPEA(N,N-ジイソプロピルエチルアミン)、TEA(トリエチルアミン)、MeI(ヨウ化メチル)、EtI(ヨウ化エチル)、TBAF(テトラブチルアンモニウムフルオリド)、TBTU(O-(ベンゾトリアゾール-1-イル)-N,N,N’,N’-テトラメチルウロニウム テトラフルオロボレート)、MsCl(塩化メタンスルホニル)、NaBH4(水素化ホウ素ナトリウム)、NaH(水素化ナトリウム)、HCl(塩化水素)、H2O(水)、PPA(ポリリン酸)、PTLC(分取薄層クロマトグラフィー)。 In the reference examples and examples, the following terms and reagents are expressed as follows.
Na 2 SO 4 (anhydrous sodium sulfate), MgSO 4 (anhydrous magnesium sulfate), Na 2 CO 3 (sodium carbonate), Cs 2 CO 3 (cesium carbonate), NaHCO 3 (sodium bicarbonate), NaOH (sodium hydroxide) , LiOH.H 2 O (lithium hydroxide monohydrate), MeOH (methanol), EtOH (ethanol), Et 2 O (diethyl ether), THF (tetrahydrofuran), DMF (N, N-dimethylformamide), MeCN (acetonitrile), EtOAc (ethyl acetate), CHCl 3 (chloroform), HOBt · H 2 O (1-hydroxybenzotriazole monohydrate), EDC · HCl [1- (3-dimethylaminopropyl) -3 -Ethylcarbodiimide monohydrochloride], HATU [O- (7- The benzotriazol-1-yl) -N, N, N ′, N′-tetramethyluronium hexafluorophosphate], DMT-MM (4- (4,6-dimethoxy-1,3,5-triazine-) 2-yl) -4-methylmorpholinium chloride), Pd (PPh 3 ) 4 [tetrakistriphenylphosphine palladium (0)], brine (saturated saline), Boc (tert-butoxycarbonyl), THP (tetrahydropyrani) ), DIPEA (N, N-diisopropylethylamine), TEA (triethylamine), MeI (methyl iodide), EtI (ethyl iodide), TBAF (tetrabutylammonium fluoride), TBTU (O- (benzotriazole-1) -Yl) -N, N, N ′, N′-tetramethyluronium tetrafluoro Rate), MsCl (methanesulfonyl chloride), NaBH 4 (sodium borohydride), NaH (sodium hydride), HCl (hydrogen chloride), H 2 O (water), PPA (polyphosphoric acid), PTLC (preparative thin Layer chromatography).
MS (ESI neg.) m/z : 242 [M-H]- (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylate (16.0 g, 62.2 mmol) in THF (497 mL) and H 2 O (124 mL) mixed solution was mixed with LiOH. H 2 O (2.74 g, 65.3 mmol) was added and stirred at room temperature overnight. After adding H 2 O and extracting with Et 2 O, 2 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with EtOAc. The resulting organic layer was dried over MgSO 4, then filtered to remove the desiccant, the solvent was distilled off under reduced pressure to give the title compound (12.7 g) (colorless solid).
MS (ESI neg.) M / z: 242 [MH]-
MS (ESI pos.) m/z : 369 [M+H]+ 4-Chloro-2-aminophenol (254 mg, 1.77 mmol) and (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (331 mg, obtained in Reference Example 1) 1.36 mmol) in EtOH (18 mL) was added DMT-MM (521 mg, 1.77 mmol), and the mixture was stirred at room temperature for 3 days. The reaction solution was concentrated, H 2 O was added, and the mixture was extracted with EtOAc. After drying over MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) to give the title compound (331 mg) (brown amorphous).
MS (ESI pos.) M / z: 369 [M + H] +
MS (ESI pos.) m/z : 351 [M+H]+ To a toluene solution (8.6 mL) of tert-butyl (2RS, 5RS) -5-[(5-chloro-2-hydroxyphenyl) carbamoyl] -2-methylpiperidine-1-carboxylate (317 mg, 0.86 mmol) Pyridine (1.39 mL, 17.2 mmol) and thionyl chloride (0.626 mL, 8.6 mmol) were added and stirred at 100 ° C. for 2 hours. Further, pyridine (1.39 mL, 17.2 mmol) and thionyl chloride (0.626 mL, 8.6 mmol) were added to the reaction solution, and the mixture was stirred at 100 ° C. for 2 hours. After allowing to cool to room temperature, H 2 O was added to the reaction mixture, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) to obtain the title compound (158 mg) (colorless amorphous).
MS (ESI pos.) M / z: 351 [M + H] +
MS (ESI pos.) m/z : 251 [M+H]+ Tert-butyl (2RS, 5RS) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1-carboxylate (160.7 mg, 0.46 mmol) in EtOAc ( (4.6 mL) was added 4 mol / L HCl-EtOAc solution (2.3 mL, 9.16 mmol), and the mixture was stirred overnight at room temperature. The reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc) to obtain the title compound (108 mg) (colorless amorphous).
MS (ESI pos.) M / z: 251 [M + H] +
MS (ESI pos.) m/z : 431 [M+H]+ (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (810 mg, 3.33 mmol) and 4-fluoro-2-aminophenol (1. 1 g, 8.66 mmol) was used as a starting material, and the title compound (799 mg) was obtained in the same manner as in Reference Example 2 (brown amorphous).
MS (ESI pos.) M / z: 431 [M + H] +
MS (ESI pos.) m/z : 335 [M+H]+ Tert-Butyl (2RS, 5RS) -5-[(5-fluoro-2-hydroxyphenyl) carbamoyl] -2-methylpiperidine-1-carboxylate (763 mg, 2.07 mmol), pyridine obtained in Reference Example 5 (6.68 mL, 41.4 mmol) and thionyl chloride (3.02 mL, 41.4 mmol) were used in the same manner as in Reference Example 2 to obtain the title compound (329 mg) (colorless amorphous).
MS (ESI pos.) M / z: 335 [M + H] +
MS (ESI pos.) m/z : 235 [M+H]+ Tert-Butyl (2RS, 5RS) -5- (5-fluoro-1,3-benzoxazol-2-yl) -2-methylpiperidine-1-carboxylate obtained in Reference Example 6 (329 mg, 0.94 mmol) ) And 4 mol / L HCl-EtOAc solution (4.7 mL, 18.8 mmol) were obtained in the same manner as in Reference Example 4 to obtain the title compound (190 mg) (colorless amorphous).
MS (ESI pos.) M / z: 235 [M + H] +
MS (ESI pos.) m/z : 297 [M+H]+ (3RS, 6RS) -6-methylpiperidine-3-carboxylate methyl (4.64 g, 29.5 mmol) and 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid ( DIPEA (20.6 mL, 118 mmol) and HATU (10.6 g, 32.5 mmol) were added to a DMF solution (295 mL) of 6.00 g, 29.5 mmol), and the mixture was stirred overnight at room temperature. Water was added to the reaction mixture, extraction was performed using EtOAc, and the organic layer was evaporated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, Hexane / EtOAc) to obtain the title compound (2.83 g) (colorless oil).
MS (ESI pos.) M / z: 297 [M + H] +
MS (ESI pos.) m/z : 329 [M+H]+ Methyl (3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylate obtained in Reference Example 8 To a 1,4-dioxane (497 mL) solution of (329 mg, 0.94 mmol) was added 2 mol / L hydrochloric acid (57.0 mL), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure, and the resulting residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) to obtain the title compound (1.41 g) (colorless amorphous).
MS (ESI pos.) M / z: 329 [M + H] +
MS (ESI pos.) m/z : 454 [M+H]+ (3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylic acid obtained in Reference Example 9 ( 300 mg, 0.91 mmol) and 4-chloro-2-aminophenol (157 mg, 1.10 mmol) were used as raw materials in the same manner as in Reference Example 8 to give the title compound (118 mg) (brown oil).
MS (ESI pos.) M / z: 454 [M + H] +
MS (ESI pos.) m/z : 438 [M+H]+ 4-Fluoro-2-aminophenol (85.2 mg, 0.67 mmol) and (3RS, 6RS) -6-methyl-1- [5-methyl-2- (2H-1, 2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylic acid (200 mg, 0.61 mmol) in DMF solution (6 mL) and HOBt · H 2 O (109 mg, 0.80 mmol) and EDC · HCl (140 mg) , 0.73 mmol) was added and stirred at room temperature overnight. To the reaction solution was added an aqueous NaHCO 3 solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) (67 mg). DIPEA (0.6 mL) was added to a DMF solution (0.6 mL) of a part of the obtained compound (26 mg), and the mixture was stirred at 100 ° C. overnight. After allowing to cool to room temperature, H 2 O was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc followed by KP-NH 11 g, CHCl 3 / MeOH) to obtain the title compound (18 mg) (colorless amorphous) .
MS (ESI pos.) M / z: 438 [M + H] +
MS (ESI pos.) m/z : 235 [M+H]+ 4-Fluoro-2-aminophenol (575 mg, 4.52 mmol), (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (1. 0 g, 4.11 mmol) and PPA (2.5 g) were stirred at 180 ° C. for 30 min. After allowing to cool to room temperature, saturated NaHCO 3 aqueous solution was added to the reaction solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (672 mg). TEA (0.70 mL, 5.02 mmol) and Boc 2 O (1.1 g, 5.02 mmol) were added to a CHCl 3 solution (13 mL) of a part of the obtained compound (608 mg) and 1.5 hours at 50 ° C. Stir. After allowing to cool to room temperature, 2 mol / L hydrochloric acid was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (333 mg). A 4 mol / L HCl-EtOAc solution (5.0 mL, 19.9 mmol) was added to an EtOAc solution (5.0 mL) of the obtained compound (333 mg, 1.00 mmol), and the mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (KP-NH 10 g, hexane / EtOAc) to obtain the title compound (196 mg) (colorless amorphous).
MS (ESI pos.) M / z: 235 [M + H] +
MS (ESI pos.) m/z : 235 [M+H]+ 4-Fluoro-2-aminophenol (575 mg, 4.52 mmol), (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (1. 0 g, 4.11 mmol) and PPA (2.5 g) were stirred at 180 ° C. for 30 min. After cooling to room temperature, NaHCO 3 aqueous solution was added to the reaction solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (560 mg). TEA (0.37 mL, 2.63 mmol) and Boc 2 O (0.57 g, 2.63 mmol) were added to a THF solution (20 mL) of the total amount of the obtained compound (560 mg), and 1 hour at 50 ° C. at room temperature for 2 hours. Stir for hours. After allowing to cool to room temperature, 2 mol / L hydrochloric acid was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc) (464 mg). A 4 mol / L HCl-EtOAc solution (7.0 mL, 27.8 mmol) was added to an EtOAc solution (5.6 mL) of the total amount of the obtained compound (464 mg, 1.39 mmol), and the mixture was stirred at room temperature for 3 hours. The resulting solid was collected by filtration to give the title compound (343 mg) (colorless solid).
MS (ESI pos.) M / z: 235 [M + H] +
MS (ESI pos.) m/z : 244 [M+H]+ A racemic mixture of methyl (3RS, 6RS) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylate (80.0 g, 329 mmol) was resolved under the racemic resolution conditions (condition 3), Two peaks (retention time: 28.5 min, 35.8 min) were separated. Of these, the title compound (34.9 g) was obtained as a compound having a long relative retention time (retention time: 35.8 min) (colorless oil). The obtained title compound was obtained by the same procedure as in Reference Examples 1, 16, 24, 32 and Example 1 [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl ) -2-Methylpiperidin-1-yl] [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone and analyzed by X-ray crystal structure analysis Its absolute steric structure was determined.
MS (ESI pos.) M / z: 244 [M + H] +
MS (ESI neg.) m/z : 242 [M-H]- (3R, 6R) -1- (tert-Butoxycarbonyl) -6-methylpiperidine-3-carboxylate (5.9 g, 22.9 mmol) in THF (183 mL) and H 2 O (46 mL) in a mixed solution of LiOH H 2 O (1.01 g, 24.1 mmol) was added and stirred at room temperature overnight. After adding H 2 O and extracting with Et 2 O, 2 mol / L hydrochloric acid was added to the aqueous layer, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (5.41 g) (colorless solid).
MS (ESI neg.) M / z: 242 [MH]-
MS (ESI pos.) m/z : 425 [M+Na]+ 5-trifluoromethyl-2-triethylsilyloxyaniline (395 mg, 1.36 mmol) and (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3- obtained in Reference Example 15 To a DMF solution (12 mL) of carboxylic acid (300 mg, 1.23 mmol) were added HOBt · H 2 O (225 mg, 1.48 mmol) and EDC · HCl (283 mg, 1.48 mmol), and the mixture was stirred overnight at room temperature. H 2 O was added to the reaction solution, and extraction was performed using Et 2 O. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was dissolved in THF (30 mL), TBAF (1.0 mol / L THF solution, 2.5 mL, 2.5 mmol) was added at room temperature, and the mixture was stirred for 2 hours. H 2 O was added, extraction was performed with EtOAc, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, hexane / EtOAc) to give the title compound (562 mg) (pale yellow oil).
MS (ESI pos.) M / z: 425 [M + Na] +
MS (ESI pos.) m/z : 385 [M+H]+ tert-Butyl (2R, 5R) -5-{[2-hydroxy-5- (trifluoromethyl) phenyl] carbamoyl} -2-methylpiperidine-1-carboxylate (494 mg, 1.23 mmol) and PPh 3 (710 mg DEAD (2.2 mol / L, 1.23 mL, 2.71 mmol) was added to a THF solution (12 mL) of (2.71 mmol) in an ice bath and stirred overnight at room temperature. After concentration under reduced pressure, the residue was purified by HPLC to give the title compound (244 mg) (pale yellow oil).
MS (ESI pos.) M / z: 385 [M + H] +
MS (ESI pos.) m/z : 285 [M+H]+ tert-Butyl (2R, 5R) -2-methyl-5- [5- (trifluoromethyl) -1,3-benzooxazol-2-yl] piperidine-1-carboxylate (244 mg, 0.635 mmol) in EtOAc To the solution (6.3 mL) was added 4 mol / L HCl-EtOAc solution (6.3 mL), and the mixture was stirred at room temperature for 30 minutes. The reaction mixture was concentrated under reduced pressure to obtain the title compound (195 mg) (colorless solid).
MS (ESI pos.) M / z: 285 [M + H] +
MS (ESI pos.) m/z : 253 [M+H]+
MS (ESI pos.) M / z: 253 [M + H] +
MS (ESI pos.) m/z : 455 [M+H]+ (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylate derived from methyl (3R, 6R) -6-methylpiperidine-3-carboxylate (165 mg, 0.78 mmol) and 3-amino-5-chloro-2-hydroxypyridine hydrochloride (143 mg, 0.79 mmol) as starting materials, and the title compound (50 mg) was obtained in the same manner as in Reference Examples 8 to 10. (Brown oil).
MS (ESI pos.) M / z: 455 [M + H] +
MS (ESI pos.) m/z : 347 [M+H]+ (3R, 6R) -1- (tert-butoxycarbonyl) -6-methyl piperidine-3-carboxylate derived from methyl (3R, 6R) -6-methylpiperidine-3-carboxylate (41.0 mg, 0.261 mmol) and 4-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoic acid (54.0 mg, 0.261 mmol) in DMF (2.61 mL) solution in DIPEA (0. 182 mL, 1.04 mmol) and HATU (102.0 mg, 0.313 mmol) were added and stirred at room temperature overnight. Aqueous NaHCO 3 solution was added to the reaction mixture, extraction was performed using CHCl 3 , and the organic layer was evaporated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil, Hexane / EtOAc) to obtain the title compound (73.0 mg) (colorless amorphous).
MS (ESI pos.) M / z: 347 [M + H] +
MS (ESI pos.) m/z : 333 [M+H]+ Methyl (3R, 6R) -1- [4-fluoro-2- (2H-1,2,3-triazol-2-yl) benzoyl] -6-methylpiperidine-3-carboxylate obtained in Reference Example 45 To a 1,4-dioxane (2.1 mL) solution of (73.0 mg, 0.21 mmol) was added 2 mol / L hydrochloric acid (2.1 mL), and the mixture was stirred at 80 ° C. for 6 hours. The reaction mixture was concentrated under reduced pressure to obtain the title compound (colorless amorphous).
MS (ESI pos.) M / z: 333 [M + H] +
MS (ESI pos.) m/z : 459 [M+H]+ (3R, 6R) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] piperidine-3-carboxylic acid obtained in Reference Example 46 0.21 mmol) and 3-amino-5-chloro-2-hydroxypyridine hydrochloride (41.82 mg, 0.23 mmol) as starting materials, and the title compound (25.5 mg) was prepared in the same manner as in Reference Example 44. Obtained (brown oil).
MS (ESI pos.) M / z: 459 [M + H] +
MS (ESI pos.) m/z : 251 [M+H]+ Using (3R, 6R) -1- (tert-butoxycarbonyl) -6-methylpiperidine-3-carboxylic acid (5.34 g, 21.95 mmol) as a starting material, the same procedure as in Reference Examples 16, 24 and 32 was performed sequentially. The reaction was performed to obtain the title compound (2.49 g) (pale yellow solid).
MS (ESI pos.) M / z: 251 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件2)で分割し、2つのピーク(前記の分析条件における保持時間:5.67min、 8.58min)を分割した。このうち相対保持時間が長い化合物(保持時間:8.58min)として表題化合物を得た(無色固体)。得られた表題化合物は、参考例14で導いて、絶対立体構造を決定した[(2R,5R)-5-(5-クロロ-1,3-ベンゾオキサゾール-2-イル)-2-メチルピペリジン-1-イル][6-メチル-3-(2H-1,2,3-トリアゾール-2-イル)ピリジン-2-イル]メタノンと、前記キラル分析(条件A)における保持時間が一致したことから、その絶対立体構造を確認した。
LCMS retention time 3.80 min.(条件3)
MS (ESI pos.) m/z : 437 [M+H]+ To a solution of 5-chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (0.30 g, 1.6 mmol) in CHCl 3 (5 mL) was added DIPEA (0. 228 mL, 1.31 mmol), 6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridine-2-carboxylic acid (66.9 mg, 0.33 mmol), propanephosphonic acid anhydride (1.7 mol / L EtOAc solution, 0.93 mL, 1.57 mmol) was added and stirred at 50 ° C. for 4.5 hours. The reaction mixture was concentrated under reduced pressure, 2 mol / L aqueous NaOH solution was added, and the mixture was extracted with EtOAc. The obtained organic layer was dried over MgSO 4 , the desiccant was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc) to obtain a racemic mixture (163 mg) of the title compound (colorless solid).
The obtained racemic mixture was divided under the above racemic resolution conditions (condition 2), and two peaks (retention times under the above analysis conditions: 5.67 min, 8.58 min) were resolved. Among these, the title compound was obtained as a compound having a long relative retention time (retention time: 8.58 min) (colorless solid). The obtained title compound was derived in Reference Example 14 and the absolute steric structure was determined [(2R, 5R) -5- (5-chloro-1,3-benzoxazol-2-yl) -2-methylpiperidine. -1-yl] [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone and the retention times in the chiral analysis (Condition A) were the same The absolute steric structure was confirmed.
LCMS retention time 3.80 min. (Condition 3)
MS (ESI pos.) M / z: 437 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.28 min.(条件3)
MS (ESI pos.) m/z : 440 [M+H]+ 5-chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (50.0 mg, 0.20 mmol) and 5-fluoro-2- (2H-1, A racemic mixture (34 mg) of the title compound was obtained in the same manner as in Example 1 using 2,3-triazol-2-yl) benzoic acid (82.6 mg, 0.40 mmol) as a raw material (colorless solid) .
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.28 min. (Condition 3)
MS (ESI pos.) M / z: 440 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.12 min.(条件3)
MS (ESI pos.) m/z : 422 [M+H]+ 5-Chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (32.8 mg, 0.13 mmol) and 2- (2H-1,2,3- A racemic mixture (37 mg) of the title compound was obtained in the same manner as in Example 1 using triazol-2-yl) benzoic acid (49.5 mg, 0.26 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.12 min. (Condition 3)
MS (ESI pos.) M / z: 422 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件2)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.52 min.(条件3)
MS (ESI pos.) m/z : 448 [M+H]+ 5-Chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (98.8 mg, 0.39 mmol) and 6-methyl-3- (pyrimidine-2- Yl) A racemic mixture of the title compound (58 mg) was obtained in the same manner as in Example 1 using pyridine-2-carboxylic acid (84.8 mg, 0.39 mmol) as a starting material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 2) to give the title compound as a compound with a long relative retention time (colorless solid).
LCMS retention time 3.52 min. (Condition 3)
MS (ESI pos.) M / z: 448 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.20 min.(条件3)
MS (ESI pos.) m/z : 447 [M+H]+ 5-chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (55.0 mg, 0.22 mmol) and 5-methyl-2- (pyrimidine-2- Il) A racemic mixture (84 mg) of the title compound was obtained in the same manner as in Example 1 using benzoic acid (94.0 mg, 0.44 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.20 min. (Condition 3)
MS (ESI pos.) M / z: 447 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.19 min.(条件3)
MS (ESI pos.) m/z : 451 [M+H]+ 5-chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (50.0 mg, 0.20 mmol) and 5-fluoro-2- (pyrimidine-2- Il) A racemic mixture (66 mg) of the title compound was obtained in the same manner as in Example 1 using benzoic acid (87.0 mg, 0.40 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.19 min. (Condition 3)
MS (ESI pos.) M / z: 451 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.98 min.(条件3)
MS (ESI pos.) m/z : 433 [M+H]+ 5-Chloro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (50.0 mg, 0.20 mmol) and 2- (pyrimidin-2-yl) benzoic acid A racemic mixture (83 mg) of the title compound was obtained in the same manner as in Example 1 using (79.8 mg, 0.40 mmol) as a starting material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 3.98 min. (Condition 3)
MS (ESI pos.) M / z: 433 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.93 min.(条件3)
MS (ESI pos.) m/z : 431 [M+H]+ 5-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (53.0 mg, 0.23 mmol) and 5-methyl-2- (pyrimidine-2- Il) A racemic mixture (55 mg) of the title compound was obtained in the same manner as in Example 1 using benzoic acid (96.9 mg, 0.45 mmol) as a raw material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 3.93 min. (Condition 3)
MS (ESI pos.) M / z: 431 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.32 min.(条件3)
MS (ESI pos.) m/z : 436 [M+H]+ (3RS, 6RS) -N- (5-chloro-2-hydroxyphenyl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazole-) obtained in Reference Example 10 A racemic mixture (65 mg) of the title compound was obtained in the same manner as in Reference Example 2 using 2-yl) benzoyl] piperidine-3-carboxamide (118 mg, 0.26 mmol) as a starting material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.32 min. (Condition 3)
MS (ESI pos.) M / z: 436 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件1)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 4.05 min.(条件3)
MS (ESI pos.) m/z : 420 [M+H]+ (3RS, 6RS) -N- (5-fluoro-2-hydroxyphenyl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazole-) obtained in Reference Example 11 A racemic mixture (65 mg) of the title compound was obtained in the same manner as in Reference Example 2 using 2-yl) benzoyl] piperidine-3-carboxamide (18 mg, 0.04 mmol) as a starting material (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 1) to obtain the title compound as a compound having a long relative retention time (colorless solid).
LCMS retention time 4.05 min. (Condition 3)
MS (ESI pos.) M / z: 420 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件2)分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.38 min.(条件3)
MS (ESI pos.) m/z : 421 [M+H]+ 5-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole (53.0 mg, 0.23 mmol) and 6-methyl-3- (2H-1, A racemic mixture (55 mg) of the title compound was obtained in the same manner as in Example 1 using 2,3-triazol-2-yl) pyridine-2-carboxylic acid (96.9 mg, 0.45 mmol) as a raw material. (Colorless solid).
The obtained racemic mixture was divided under the above racemic resolution conditions (Condition 2) to give the title compound as a compound with a long relative retention time (colorless solid).
LCMS retention time 3.38 min. (Condition 3)
MS (ESI pos.) M / z: 421 [M + H] +
得られたラセミ混合物を前記のラセミ体分割条件(条件2)で分割し、相対保持時間が長い化合物として表題化合物を得た(無色固体)。
LCMS retention time 3.36 min.(条件3)
MS (ESI pos.) m/z : 421 [M+H]+ 6-Fluoro-2-[(3RS, 6RS) -6-methylpiperidin-3-yl] -1,3-benzoxazole hydrochloride (88.0 mg, 0.33 mmol), TEA (0.05 mL, 0.36 mmol) ) In DMF solution (3 mL), 6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridine-2-carboxylic acid (73.0 mg, 0.36 mmol), HOBt · H 2 O (74.0 mg, 0.49 mmol) and EDC.HCl (93.0 mg, 0.49 mmol) were added, and the mixture was stirred at room temperature for 3 hours. To the reaction solution was added an aqueous NaHCO 3 solution, and the mixture was extracted with EtOAc. After drying the organic layer with MgSO 4 , the desiccant was filtered off and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc) to obtain a racemic mixture (32 mg) of the title compound (colorless solid).
The obtained racemic mixture was divided under the above-mentioned racemic resolution conditions (Condition 2) to give the title compound as a compound with a long relative retention time (colorless solid).
LCMS retention time 3.36 min. (Condition 3)
MS (ESI pos.) M / z: 421 [M + H] +
LCMS retention time 1.16 min.(条件4)
MS (ESI pos.) m/z : 467 [M+H]+ 5-chloro-2-[(3R, 6R) -6-methylpiperidin-3-yl] -1,3-benzoxazole (20 mg, 0.080 mmol) and 5-chloro-2- (pyrimidin-2-yl) Benzoic acid (19 mg, 0.080 mmol) in CHCl 3 (1 mL) in DIPEA (34.7 μL, 0.20 mmol) and propanephosphonic acid anhydride (1.7 mmol / L, EtOAc solution, 141 μL, 0.24 mmol) And stirred at 50 ° C. for 9 hours. To the reaction solution was added an aqueous NaHCO 3 solution, and the mixture was extracted with CHCl 3 . The reaction mixture was concentrated under reduced pressure and purified by HPLC to give the title compound (4.9 mg) (yellow solid).
LCMS retention time 1.16 min. (Condition 4)
MS (ESI pos.) M / z: 467 [M + H] +
LCMS retention time 1.03 min.(条件4)
MS (ESI pos.) m/z : 437(M+H)+ (3R, 6R) -N- (5-Chloro-2-hydroxypyridin-3-yl) -6-methyl-1- [5-methyl-2- (2H-1,2,3-triazol-2-yl) ) Benzoyl] piperidine-3-carboxamide (50 mg, 0.11 mmol), PPh 3 (87 mg, 0.33 mmol), C 2 Cl 6 (65 mg, 0.27 mmol), TEA (120 μL, 0.88 mmol) in CHCl 3 (2 mL) was stirred at room temperature overnight. After concentration under reduced pressure, the residue was purified by HPLC to give the title compound (17 mg) (colorless solid).
LCMS retention time 1.03 min. (Condition 4)
MS (ESI pos.) M / z: 437 (M + H) +
LCMS retention time 1.01 min.(条件4)
MS (ESI pos.) m/z : 463 (M+Na)+
LCMS retention time 1.01 min. (Condition 4)
MS (ESI pos.) M / z: 463 (M + Na) +
試験化合物のヒトオレキシン1型受容体(hOX1R)、オレキシン2型受容体(hO
X2R)に対する拮抗活性は文献(Toshikatsu Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001)に記載された方法を改変して行った。hOX1R、hOX2Rを強制発現させたChinese hamster ovary(CHO)細胞を96wellのBlack clear bottomプレート(Nunc)の各ウェルに20,000個となるように播種し、0.1mM MEM非必須アミノ酸、0.5mg/ml G418、10% 牛胎児血清を含むHam’s F-12培地(以上インビトロジェン)で、37℃、5% CO2の条件下で16時間培養した。培地を除去後、0.5μM Fluo-3AM エステル(同仁)を含むアッセイ用緩衝液(25mM HEPES(同仁)、Hanks’ balanced salt solution(インビトロジェン)、0.1% 牛血清アルブミン、2.5mM プロベネシド、200μg/ml Amaranth(以上Sigma-Aldrich)、pH7.4)を100μL添加し60分間、37℃、5% CO2にインキュベートした。Fluo-3AM エステルを含むアッセイ用緩衝液を除去したのち、試験化合物は10mMとなるようにジメチルスルホキシドで溶解してアッセイ用緩衝液で希釈後、150μLを添加し、30分間インキュベートした。
リガンドであるヒトオレキシン-Aの2アミノ酸を置換したペプチド(Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu-Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2;ペプチド研究所)はhOX1Rに対しては終濃度300pM、hOX2Rに対しては3nMとなるようにアッセイ用緩衝液で希釈し、このリガンド溶液50μLを添加して反応を開始した。反応はFunctional Drug Screening System(FDSS;浜松ホトニクス社製)を用いて各wellの蛍光値を1秒毎に3分間測定し、最大蛍光値を細胞内Ca2+濃度の指標として拮抗活性を求めた。試験化合物の拮抗活性は希釈緩衝液のみを添加したウェルの蛍光値を100%、リガンドおよび化合物を含まない緩衝液を添加したウェルの蛍光値を0%として算出し、種々の濃度の試験化合物を添加した際の蛍光値から、50%阻害濃度(IC50値)を求めた。 Test Example 1 (Measurement of orexin antagonistic activity)
Test compounds human orexin type 1 receptor (hOX1R), orexin type 2 receptor (hO
The antagonistic activity against (X2R) was performed by modifying the method described in the literature (Toshikatsu Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001). Chinese hamster ovary (CHO) cells in which hOX1R and hOX2R are forcibly expressed were seeded in each well of a 96-well Black clear bottom plate (Nunc) at 20,000 cells, 0.1 mM MEM non-essential amino acids, 0. The cells were cultured in Ham's F-12 medium (Invitrogen) containing 5 mg / ml G418, 10% fetal calf serum for 16 hours under conditions of 37 ° C. and 5% CO 2. After removing the medium, an assay buffer containing 25 μM Fluo-3AM ester (Dojin) (25 mM HEPES (Dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 2.5 mM probenecid, 100 μL of 200 μg / ml Amaranth (above Sigma-Aldrich), pH 7.4) was added and incubated for 60 minutes at 37 ° C., 5% CO 2 . After removing the assay buffer containing Fluo-3AM ester, the test compound was dissolved in dimethyl sulfoxide to a concentration of 10 mM, diluted with assay buffer, added with 150 μL, and incubated for 30 minutes.
Peptide substituted with 2 amino acids of human orexin-A ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu -Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2 (Peptide Institute) is a final concentration of 300 pM for hOX1R and hOX2R Each was diluted with an assay buffer so as to be 3 nM, and 50 μL of this ligand solution was added to initiate the reaction. For the reaction, the fluorescence value of each well was measured for 3 minutes every second using a Functional Drug Screening System (FDSS; manufactured by Hamamatsu Photonics), and the antagonistic activity was determined using the maximum fluorescence value as an index of intracellular Ca 2+ concentration. The antagonistic activity of the test compound was calculated by setting the fluorescence value of the well to which only the dilution buffer was added to 100% and the fluorescence value of the well to which the buffer solution containing no ligand and compound was added to 0%. The 50% inhibitory concentration (IC 50 value) was determined from the fluorescence value upon addition.
被験化合物のヒト肝ミクロソーム(Ms)における安定性試験は以下の方法に従って行った。
被験化合物を、NADPH 生成系(0.16mM NADP+、2.5mM MgCl2、1.5mM glucose-6-phosphate)存在下、ヒト肝ミクロソーム画分(Xenotech/H630B/lot.0810472)とともに0.1M リン酸緩衝液(pH7.4)中でインキュベートした(37℃,15分間)。被験化合物、肝Msタンパクの終濃度は,それぞれ1μM及び0.25mg protein/mLとした。インキュベート後の反応混液は、2倍容量のDMSOを添加、攪拌したのち2150xgで遠心分離した(4℃,10分間)。得られた上清は、液体クロマトグラフィータンデム質量分析(LC-MS/MS)システムによる分析に供した。定量下限は、0.1μMであった。その結果、実施例1の化合物の代謝率は27.8%であった。 Test Example 2 (Metabolic stability test)
The stability test of the test compound in human liver microsomes (Ms) was performed according to the following method.
The test compound was added with 0.1 M phosphoric acid together with human liver microsome fraction (Xenotech / H630B / lot.0810472) in the presence of NADPH production system (0.16 mM NADP +, 2.5 mM MgCl2, 1.5 mM glucose-6-phosphate). Incubated in buffer (pH 7.4) (37 ° C., 15 minutes). The final concentrations of the test compound and liver Ms protein were 1 μM and 0.25 mg protein / mL, respectively. The reaction mixture after the incubation was added with 2 volumes of DMSO, stirred, and then centrifuged at 2150 × g (4 ° C., 10 minutes). The obtained supernatant was subjected to analysis by a liquid chromatography tandem mass spectrometry (LC-MS / MS) system. The lower limit of quantification was 0.1 μM. As a result, the metabolic rate of the compound of Example 1 was 27.8%.
Claims (12)
- 式(IA)
Xは、窒素原子、又は式CHを示し、
Yは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基(該C1-6アルキル基は、1~3個のハロゲン原子で置換されてもよい)、又はC1-6アルコキシ基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1~3個の置換基で置換されてもよい)を示し、
R3及びR4は、同一に又は異なって、水素原子、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1~3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩。 Formula (IA)
X represents a nitrogen atom or the formula CH;
Y represents a nitrogen atom or the formula CH;
R 1 represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group (the C 1-6 alkyl group may be substituted with 1 to 3 halogen atoms), or C 1-6 alkoxy Group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with the same or different 1 to 3 substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group);
R 3 and R 4 are the same or different and each represents a hydrogen atom, a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and C 1-6 The alkoxy group may be substituted with 1 to 3 halogen atoms). )
Or a pharmaceutically acceptable salt thereof. - 上記式(IA)において、
R3が、ハロゲン原子、シアノ基、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1~3個のハロゲン原子で置換されてもよい)であり、
R4が、水素原子、又はハロゲン原子である請求項1に記載のメチルピペリジン誘導体、又はその医薬上許容される塩。 In the above formula (IA),
R 3 is a halogen atom, a cyano group, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be)
The methylpiperidine derivative according to claim 1, or a pharmaceutically acceptable salt thereof, wherein R 4 is a hydrogen atom or a halogen atom. - 上記式(IA)において、
R2が、トリアゾリル基、又はピリミジニル基(該ピリミジニル基は、ハロゲン原子及びC1-6アルコキシ基からなる群から選ばれる同一又は異なった1~3個の置換基で置換されてもよい)である請求項1又は2いずれかに記載のメチルピペリジン誘導体、又はその医薬上許容される塩。 In the above formula (IA),
R 2 is a triazolyl group or a pyrimidinyl group (the pyrimidinyl group may be substituted with 1 to 3 identical or different substituents selected from the group consisting of a halogen atom and a C 1-6 alkoxy group). The methyl piperidine derivative according to claim 1 or 2, or a pharmaceutically acceptable salt thereof. - 上記式(IA)において、
R1が、水素原子、ハロゲン原子、又はC1-6アルキル基である請求項1~3いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩。 In the above formula (IA),
The methylpiperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 3, wherein R 1 is a hydrogen atom, a halogen atom, or a C 1-6 alkyl group. - 上記式(IA)において、
Yが、式CHであり、
R2が、トリアゾリル基、又はピリミジニル基である請求項1~4いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩。 In the above formula (IA),
Y is the formula CH;
The methylpiperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 4, wherein R 2 is a triazolyl group or a pyrimidinyl group. - 上記式(IA)において、
Xが、窒素原子であり、
R4が、水素原子である請求項1~5いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩。 In the above formula (IA),
X is a nitrogen atom,
6. The methylpiperidine derivative or a pharmaceutically acceptable salt thereof according to any one of claims 1 to 5, wherein R 4 is a hydrogen atom. - 式(I)
Xは、窒素原子、又は式CHを示し、
R1は、水素原子、ハロゲン原子、又はC1-6アルキル基を示し、
R2は、ヘテロアリール基(該ヘテロアリール基は、1~3個のハロゲン原子で置換されてもよい)を示し、
R3は、水素原子、ハロゲン原子、C1-6アルキル基、又はC1-6アルコキシ基(該C1-6アルキル基、及びC1-6アルコキシ基は1~3個のハロゲン原子で置換されてもよい)を示す。)
で表されるメチルピペリジン誘導体、又はその医薬上許容される塩。 Formula (I)
X represents a nitrogen atom or the formula CH;
R 1 represents a hydrogen atom, a halogen atom, or a C 1-6 alkyl group,
R 2 represents a heteroaryl group (the heteroaryl group may be substituted with 1 to 3 halogen atoms);
R 3 represents a hydrogen atom, a halogen atom, a C 1-6 alkyl group, or a C 1-6 alkoxy group (the C 1-6 alkyl group and the C 1-6 alkoxy group are substituted with 1 to 3 halogen atoms) May be). )
Or a pharmaceutically acceptable salt thereof. - 上記式(I)において、
Xが、窒素原子であり、
R1が、水素原子、又はC1-6アルキル基であり、
R2が、トリアゾリル基、又はピリミジニル基であり、
R3が、ハロゲン原子である請求項8に記載のメチルピペリジン誘導体、又はその医薬上許容される塩。 In the above formula (I),
X is a nitrogen atom,
R 1 is a hydrogen atom or a C 1-6 alkyl group,
R 2 is a triazolyl group or a pyrimidinyl group;
The methylpiperidine derivative according to claim 8, or a pharmaceutically acceptable salt thereof, wherein R 3 is a halogen atom. - 請求項1~10いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有する医薬。 A medicament comprising the methylpiperidine derivative according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient.
- 請求項1~10いずれか1項に記載のメチルピペリジン誘導体、又はその医薬上許容される塩を有効成分として含有する睡眠障害、うつ病、不安障害、パニック障害、統合失調症、薬物依存症、アルツハイマー病、パーキンソン病、ハンチントン舞踏病、摂食障害、頭痛、片頭痛、疼痛、消化器疾患、てんかん、炎症、免疫関連疾患、内分泌関連疾患、又は高血圧の疾患の治療又は予防薬。 Sleep disorder, depression, anxiety disorder, panic disorder, schizophrenia, drug dependence, containing the methylpiperidine derivative according to any one of claims 1 to 10 or a pharmaceutically acceptable salt thereof as an active ingredient, A therapeutic or prophylactic agent for Alzheimer's disease, Parkinson's disease, Huntington's disease, eating disorders, headache, migraine, pain, digestive disorders, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, or hypertension.
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JPWO2013005755A1 (en) | 2015-02-23 |
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